REVIEW PAPER

Genetic syndromes caused by mutations in epigenetic genes

Marıa Berdasco • Manel Esteller

Received: 10 December 2012 / Accepted: 18 January 2013 / Published online: 31 January 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract The orchestrated organization of epigenetic

factors that control chromatin dynamism, including DNA

methylation, histone marks, non-coding RNAs (ncRNAs)

and chromatin-remodeling proteins, is essential for the

proper function of tissue homeostasis, cell identity and

development. Indeed, deregulation of epigenetic profiles

has been described in several human pathologies, including

complex diseases (such as cancer, cardiovascular and

neurological diseases), metabolic pathologies (type 2 dia-

betes and obesity) and imprinting disorders. Over the last

decade it has become increasingly clear that mutations of

genes involved in epigenetic mechanism, such as DNA

methyltransferases, methyl-binding domain proteins, his-

tone deacetylases, histone methylases and members of the

SWI/SNF family of chromatin remodelers are linked to

human disorders, including Immunodeficiency Centro-

meric instability Facial syndrome 1, Rett syndrome,

Rubinstein–Taybi syndrome, Sotos syndrome or alpha-

thalassemia/mental retardation X-linked syndrome, among

others. As new members of the epigenetic machinery are

described, the number of human syndromes associated with

epigenetic alterations increases. As recent examples, muta-

tions of histone demethylases and members of the non-

coding RNA machinery have recently been associated with

Kabuki syndrome, Claes-Jensen X-linked mental retardation

syndrome and Goiter syndrome. In this review, we describe

the variety of germline mutations of epigenetic modifiers that

are known to be associated with human disorders, and dis-

cuss the therapeutic potential of epigenetic drugs as pallia-

tive care strategies in the treatment of such disorders.

Introduction

Chromatin dynamism is critical to basic cellular processes

such as gene transcription, DNA replication, DNA

recombination and DNA repair. DNA accessibility is

modulated by epigenetic mechanisms that ultimately alter

the structure of the chromatin and provide binding sites

for a wide variety of regulatory proteins. The orchestrated

organization of epigenetic factors, including DNA meth-

ylation, histone marks, non-coding RNAs (ncRNAs), and

their associated chromatin proteins, is essential for

development and cellular differentiation. For instance,

extensive chromatin remodeling occurs on a global level

during early development. DNA methylation patterns

undergo genome-wide alterations that occur immediately

after fertilization and during early-preimplantation devel-

opment, together with histone modification changes, such

as increased H3K9me with differentiation (Reik 2007).

Epigenetic factors also guarantee the activation and

maintenance of specific differentiation programs in adult

somatic cells (Berdasco and Esteller 2010). The active

role of epigenetic factors in controlling cellular differen-

tiation is supported by spontaneous cell differentiation

after treatment with demethylating agents or histone

M. Berdasco � M. Esteller (&)

Cancer Epigenetics Group, Cancer Epigenetics and Biology

Program (PEBC), Bellvitge Biomedical Research Institute

(IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran

Via 199-203, 08908 L’Hospitalet de LLobregat Barcelona,

Catalonia, Spain

e-mail: mesteller@idibell.cat

M. Esteller

Department of Physiological Sciences II, School of Medicine,

University of Barcelona, Barcelona, Catalonia, Spain

M. Esteller

Institucio Catalana de Recerca I Estudis Avancats (ICREA),

08010 Barcelona, Catalonia, Spain

123

Hum Genet (2013) 132:359–383

DOI 10.1007/s00439-013-1271-x

deacetylase inhibitors (reviewed in Berdasco and Esteller

2011). Treatment with the demethylation agent 5-aza-20-deoxycytidine promotes differentiation of different types

of adult stem cells into cardiac myogenic or osteogenic

cells by enhancing the expression of lineage genes. In a

similar manner, histone deacetylase inhibitor trichostatin

enhances chondrogenic or neural differentiation of stem

cells, reinforcing the epigenetic control of differentiation.

Furthermore, the essential role of these factors is reflected

in the fact that altered profiles of epigenetic marks often

lead to defaults in cellular homeostasis and development

of human diseases. Genetic alterations could explain the

causes of several monogenic diseases. However, the

genetic basis underlying the origin of complex and mul-

tifactorial diseases remains largely unknown and the

importance of the role of non-genetic mechanisms,

including epigenetic mechanisms or posttranslational

protein modifications, is increasingly being realized.

Cancer has been the best characterized complex human

disease associated with epigenetic defects (Berdasco and

Esteller 2010), but the list of complex diseases carrying

epigenetic defaults has been increasing rapidly in recent

years. Epigenetic studies have now been made of complex

diseases such as obesity, type 2 diabetes mellitus, car-

diovascular diseases and neurological disorders. These

pathogenic mechanisms are particularly interesting

because the epigenetic effects may also be affected by

aspects of the environment such as diet and lifestyle,

raising the possibility of ‘‘resetting’’ the altered epigenetic

marks. Deleterious epigenetic profiles could be a conse-

quence of mutations in the ‘‘writers’’, that is to say,

dysfunctional enzymes that are responsible for putting in

and out the epigenetic marks. Defective epigenetic

machinery has been observed in cancer initiation and

progression. Furthermore, germline mutations of epige-

netic modifiers contribute to the development of human

diseases including intellectual disability (review in: Fro-

yen et al. 2006; Kramer and van Bokhoven 2009;

Franklin and Mansuy 2011). The aim of the present

review is to provide an overview of these disorders

grouped by the type of epigenetic change involved:

(i) alterations in DNA methylation players; (ii) mutations

in histone modifiers; (iii) disruption of chromatin-remod-

eling complexes, and (iv) mutations in non-coding RNA

processing machinery.

Genetic disorders linked to DNA methylation defects

DNA methylation, or the addition of a methyl group to a

cytosine, is a key epigenetic player that has long been

considered the genome’s fifth base (Portela and

Esteller 2010). In mammals this reaction occurs at CpG

(deoxycytidine-phosphate-deoxyguanosine) sites located

throughout the genome, but there are certain areas, known

as CpG islands, that are enriched in CpG dinucleotides

(especially in promoter regions). Non-CpG islands of the

human genome are usually methylated and prevent geno-

mic instability phenomena, such as the movement of

transposable elements (Berdasco and Esteller 2010). Nor-

mal methylation at these sequences is also necessary for

X-chromosome inactivation in females and genomic

imprinting. Conversely, CpG islands are usually unme-

thylated, being closely related to the expression of house-

keeping genes. It is estimated that only 6 % of the human

CpG islands are methylated and, consequently, silenced,

being essential for maintaining tissue-specific patterns

during development and differentiation. By our current

understanding, this ‘‘DNA methylation code’’ seems to be

an oversimplification, since, in recent years, new genomic

contexts outside of CpG islands, known as CpG shores,

have emerged as candidates for regulating gene expression

of tissue-specific genes. The technological advance in

studying DNA methylation will provide insight into the

role of 5-methylcytosine patterns with respect to their

density, location and function, amongst other features.

Additionally the recently discovered cytosine modification

5-hydroxymethyl-20-deoxycytidine (5hmC) needs to be

further studied to determine its implications for normal and

diseased epigenetic regulation.

The enzymes responsible for introducing the methyl

group into a cytosine are DNA methyltransferases

(DNMTs). Three major proteins with DNMT activity have

been identified in mammals: DNMT1, DNMT3A and

DNMT3B. DNMT1 is a widely expressed maintenance

DNMT that recognizes hemimethylated DNA and is

responsible for maintaining the existing methylation pat-

terns after DNA replication. By contrast, DNMT3 enzymes

are de novo DNMTs that introduce methyl groups into

previously unmethylated cytosines. These enzymes intro-

duce a methyl group into the genome, but this ‘‘writing’’

must be interpreted (read) by the rest of the cellular

machinery (i.e., transcription factors, DNA polymerases,

chromatin-remodeling proteins, epigenetic enzymes, etc.).

Additional members of the DNMT family without meth-

yltransferase activity have been reported, such as DNMT2

or DNMT3L. DNMT3L lacks the amino acid sequence

necessary for methyltransferase but it seems to be required

for the establishment of maternal genomic imprints

(Aapola et al. 2002).

Methyl-CpG-binding domain (MBD) proteins are one of

the DNA methylation-associated proteins that could be

recruited to methylated DNA and in turn facilitate the

recruitment of histone modifiers and chromatin-remodeling

complexes (Portela and Esteller 2010). Evidence is

mounting of the role of DNA methylation in modulating

360 Hum Genet (2013) 132:359–383

123

cognitive functions of the central nervous system, such as

learning and memory, and of how dysregulation of DNMTs

activities can give rise to neurological disorders (Liu et al.

2009; Urdinguio et al. 2009; Feng et al. 2010). Some of the

genetic syndromes featuring mutations in the DNA-related

machinery that often cause neurological disorders are dis-

cussed in this section (Table 1).

DNMT1 mutations and disorders of the central

and peripheral nervous system

Hereditary sensory and autonomic neuropathy type 1 with

dementia and hearing loss (HSAN1; MIM #614116) is a

degenerative disorder of the central and peripheral nervous

system. Its clinical manifestations consist of sensory

impairment, sudomotor dysfunction (loss of sweating),

dementia and sensorineural hearing loss. HSAN1 is

inherited in an autosomal dominant manner, although the

proportion of patients with de novo mutations is unknown,

DNMT1 being the only gene in which mutations of exons

20 and 21 are known to cause HSAN1 (Klein et al. 2011;

Winkelmann et al. 2012). Molecular genetic testing to

screen for three mutations in exon 21 of DNMT1

(p.Ala570Val, p.Gly605Ala and p.Val606phe) is available

for research purposes. Mutations are present within the

targeting-sequence domain of DNMT1 that regulates the

binding of the enzyme to chromatin during the S-phase and

is responsible for maintaining this association during the

G2-M phases (Fatemi et al. 2001; Song et al. 2012).

DNMT1 is strongly expressed in postmitotic neurons and

plays important roles in neuronal differentiation, migration

and central neural connection (Feng et al. 2010). The

functional involvement of DNMT1 mutations has been

assessed in in vitro studies in HeLa cells (Klein et al.

2011), so that cells carrying mutations in the DNMT1

targeting sequence showed abnormal heterochromatin

binding of DNMT1 during the G2 phase and were pre-

maturely degraded. Abolishing DNMT1 function affects

DNA methylation cellular levels: first, a lower level of

global methylation (8 %) has been measured in mutant

cells (i.e., satellite 2 methylation was reduced); second,

site-specific hypermethylation at specific loci has also been

found (Klein et al. 2011). Additionally, DNMT1 is required

for CD4? differentiation into T regulatory cells (Jose-

fowicz et al. 2009), and a link between the absence of

CD4? T regulatory cells and the autoimmune response in

neurological syndromes has been proposed (Winkelmann

et al. 2012). The findings from several studies together

suggest that DNMT1 participates in a precise mechanism

of dynamic regulation of neuronal survival, but additional

efforts will be needed to elucidate its pathogenic mecha-

nisms and to explain the phenotypic variation observed

between individuals bearing different mutations.

DNMT3 mutations and immunodeficiency centromeric

instability facial syndrome 1

Immunodeficiency centromeric instability facial syndrome

1 (ICF1, MIM #242860) is a rare autosomal recessive

disorder characterized by immune defects in association

with centromere instability and facial anomalies. Several

chromosomal abnormalities have been described, including

the juxtacentromeric heterochromatin formation of chro-

mosomes 1, 9 and 16, an increased frequency of somatic

recombination between the arms of these chromosomes,

and a marked tendency to form multibranched configura-

tions (Ehrlich 2003). 60 % of ICF1 patients carry muta-

tions in the de novo DNA methyltransferase DNMT3B

(Xu et al. 1999; Lana et al. 2012). Mutations in the ZBTB24

gene, which encodes a transcription factor, are responsible

for the ICF type 2 phenotype (de Greef et al. 2011).

Hypomethylation in ICF patients commonly affect specific

non-coding repetitive sequences (satellites 2 and 3, subt-

elomeric sequences and Alu sequences), imprinted genes

and genes located in constitutive and facultative hetero-

chromatin (Xu et al. 1999; Yehezkel et al. 2008; Brun et al.

2011), causing chromatin decondensation and chromosome

instability. Recently, whole-genome bisulfite sequencing of

an ICF patient harboring mutated DNMT3B and one heal-

thy control have been performed to assess DNA methyla-

tion at base pair resolution (Heyn et al. 2012). The authors

concluded that ICF patients have 42 % less global DNA

methylation, especially in inactive heterochromatic regions

(in accordance with previous studies). Interestingly, the

methylation status of transcriptional active loci and rRNA

repeats did not change, suggesting that there is a selective

pressure to maintain the stability of these genomic struc-

tures (Heyn et al. 2012). In addition to methylation studies,

the altered expression of more than 700 genes in ICF1

patients has been described, especially genes related to

immune function, development and neurogenesis (Jin et al.

2008). Interestingly, half the upregulated genes were hy-

pomethylated (compared with normal cells) in parallel with

the loss of the histone repressive H3K27 trimethylation

mark and the gain of the histone active marks H3K9

acetylation and H3K4 trimethylation (Jin et al. 2008). Not

only the protein-coding genes are altered; a dramatic loss

of methylation (from 80 to 30 %) was found in hetero-

chromatic genes, which are usually aberrantly hypome-

thylated in cancer cells, although the hypomethylation was

not always associated with their activation (Brun et al.

2011). In contrast to the dysregulation of protein-coding

genes, no changes in histone marks associated with het-

erochromatic genes could be found (Brun et al. 2011).

Finally, the genomic instability generated in ICF patients

also resulted in replication defects, including shortening of

the S-phase, a higher global replication fork speed and

Hum Genet (2013) 132:359–383 361

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Table 1 List of human disorders associated with germline mutations in epigenetic genes

Gene GeneIDa Cytogenetic

location

Function Disease OMIMb References

Mutations associated with DNA methylation

DNMT1 1786 19p13.2 DNMT Hereditary sensory and autonomic neuropathy type 1

(HSAN1)

614116 Klein et al. (2011),

Winkelmann et al.

(2012)

DNMT3b 1789 20q11.21 DNMT Immunodeficiency–centromeric instability–facial

anomalies syndrome 1 (ICF1)

242860 Xu et al. (1999);

Lana et al. (2012)

MECP2 4204 Xq28 MDB Rett syndrome 312750 Amir et al. (1999),

Moretti and Zoghbi

(2006)

MECP2 4204 Xq28 MDB Angelman syndrome 105830 Watson et al. (2001)

Mutations associated with histone modifications

MYST4 23522 10q22.2 HAT Genitopatellar syndrome 606170 Campeau et al.

(2012a), Simpson

et al. (2012)

MYST4 23522 10q22.2 HAT Say-Barber-Biesecker-Young-Simpson syndrome

(SBBYS)

603736 Clayton-Smith et al.

(2011)

CREBBP 1387 16p13.3 HAT Rubinstein–Taybi syndrome 1 180849 Petrij et al. (1995),

Tsai et al. (2011)

EP300 2033 22q13.2 HAT Rubinstein–Taybi syndrome 2 613684 Arany et al. (1994),

Bartsch et al.

(2010)

HDAC4 14063 2q37.3 HDAC Brachydactyly-mental retardation syndrome

(BDMR)

600430 Williams et al.

(2010), Morris

et al. (2012)

EHMT1 79813 9q34.3 HMT Kleefstra syndrome 610253 Kleefstra et al.

(2009)

EZH2 2146 7q36.1 HMT Weaver syndrome 2 (WVS2) 614421 Gibso et al. (2012)

MLL2 8085 12q13.12 HMT Kabuki syndrome 1 147920 Ng et al. (2010),

Hannibal et al.

(2011)

NSD1 64324 5q35.2 HDMT Sotos syndrome 117550 Tatton-Brown and

Rahman (2007)

NSD1 64324 5q35.2 HDMT Weaver syndrome 1 (WVS1) 277590 Douglas et al. (2003)

NSD1 64324 5q35.2 HDMT Beckwith–Wiedemann syndrome 130650 Baujat et al. (2004)

JMJD3 7403 Xp11.3 HDMT Kabuki syndrome 2 300867 Lederer et al. (2012)

PHF8 23133 Xp11.22 HDMT Siderius X-Linked Mental Retardation Syndrome

(MRXSSD)

300263 Laumonnier et al.

(2005), Koivisto

et al. (2007)

JARID1C 8242 Xp11.22 HDMT Claes-Jensen X-linked Mental retardation syndrome 300534 Claes et al. (2000),

Jensen et al. (2005)

Mutations associated with chromatin- remodeling factors

ATXN7 6314 3p14.1 STAGA-

HAT

complex

Spinocerebellar ataxia 7 164500 Garden and La

Spada (2008)

ATRX 546 Xq21.1 SWI/SNF

complex

Alpha-thalassemia X-linked mental retardation

syndrome

301040 Gibbons et al. (1995)

ATRX 546 Xq21.1 SWI/SNF

complex

Mental retardation-hypotonic facies syndrome,

X-linked

309580 Abidi et al. (2005)

ATRX 546 Xq21.1 SWI/SNF

complex

Alpha-thalassemia myelodysplasia syndrome 300448 Gibbons et al. (2003)

ERCC6 2074 10q11.23 SWI/SNF

complex

Cockayne syndrome, type B (CSB) 133540 Laugel et al. (2010)

ERCC8 1161 5q12.1 SWI/SNF

complex

Cockayne syndrome, type A (CSA) 216400 Henning et al. (1995)

362 Hum Genet (2013) 132:359–383

123

earlier replication of heterochromatic genes in S-phase

(Lana et al. 2012). To conclude, the loss of DNMT3B

function and the interaction of DNMT3B with histone

modifications, together with the variable clinical features

of the patients, make ICF samples an ideal model for

investigating the epigenetic network and their molecular

consequences in several biological pathways (gene tran-

scription, DNA replication and recombination, among

others).

MeCP2 genetic alterations and Rett syndrome

Rett syndrome (MIM #312750) is a progressive neurode-

velopmental disorder characterized by arrested develop-

ment between 6 and 18 months of age, regression of

acquired skills, loss of speech, unusual stereotyped move-

ments and intellectual disability (Zachariah and Rastegar

2012). It affects predominantly females, occurring at a

frequency of 1:10,000 live births, but male patients with

Rett syndrome and variable phenotype (i.e., severe to

moderate congenital encephalopathy, infantile death or

psychiatric manifestations) have also been described (Ravn

et al. 2003; Moretti and Zoghbi 2006). Mutations in the

X-linked gene encoding methyl-CpG-binding protein 2

(MeCP2), including missense, frameshift and nonsense

mutations and intragenic deletions, account for the condi-

tion in up to 96 % of Rett syndrome patients (Amir et al.

1999; Moretti and Zoghbi 2006). Interestingly, the increase

in MeCP2 dosage due to duplications of the locus and

surrounding areas also causes the neurological disorder

Lubs X-linked mental retardation syndrome (MRXSL,

MIM #300260) (Van Esch et al. 2005). MeCP2 mutations

in Rett syndrome patients arise in the germline although the

phenotypic alterations in the neurological system appear at

Table 1 continued

Gene GeneIDa Cytogenetic

location

Function Disease OMIMb References

SMARCB1 6598 22q11.23 SWI/SNF

complex

Coffin-Siris syndrome 135900 Tsurusaki et al.

(2012)

SMARCA4 6597 19p13.2 SWI/SNF

complex

Coffin-Siris syndrome 135900 Tsurusaki et al.

(2012)

SMARCA2 6596 9p24.3 SWI/SNF

complex

Coffin-Siris syndrome 135900 Tsurusaki et al.

(2012)

SMARCA2 6596 9p24.3 SWI/SNF

complex

Nicolaides-Baraitser syndrome 601358 Van Houdt et al.

(2012)

ARID1A 8289 1p36.11 SWI/SNF

complex

Coffin-Siris syndrome 135900 Tsurusaki et al.

(2012)

ARID1B 57492 6q25.3 SWI/SNF

complex

Coffin-Siris syndrome 135900 Tsurusaki et al.

(2012)

SRCAP 10847 16p11.2 SRCAP

complex

Floating-Harbor syndrome 136140 Hood et al.

(2012)

CDH7 55636 8q12.1 CHD

complex

Coloboma of the eye, Heart Anomaly, choanal

Atresia, Retardation, Genital And Ear Anomalies

syndrome (CHARGE)

214800 Sanlaville et al.

(2006)

CDH7 55636 8q12.1 CHD

complex

Hypogonadotropic hypogonadism 2 with or without

anosmia

147950 Kim et al.

(2008)

Mutations associated with non-coding RNAs

DICER1 23405 14q32.13 miRNA

processing

Goiter, multinodular 1, with or without Sertoli-

Leydig cell tumors

138800 Rio Frio et al.

(2011)

TDP-43 23435 1p36.22 miRNA

processing

Amyotrophic lateral sclerosis 612069 Ling et al.

(2010)

FMRP 2332 Xq27.3 miRNA

processing

Fragile X syndrome 300624 Edbauer et al.

(2010)

DGCR8 54487 22q11.21 miRNA

processing

DiGeorge syndrome 188400 Shiohama et al.

(2003), Stark et al.

(2008)

CHD chromodomain helicase DNA-binding protein, DNMT DNA methyltransferase, HAT histone acetyltransferase, HDAC histone deacetylase,

HDMT histone demethylase, MDB methyl DNA-binding domain protein, HMT histone methyltransferase, SRCAP Snf2-related CREBBP

activator protein, STAGA SPT3/TAF9/GCN5 transcription coactivator complex, SWI/SNF SWItch/sucrose non fermentablea Identification in Entrez Gene database (http://www.ncbi.nlm.nih.gov/gene)b Identification in Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/)

Hum Genet (2013) 132:359–383 363

123

early postnatal stages (Zachariah and Rastegar 2012).

Recently, abrogation of MeCP2 function in adult mice has

been found to result in severe neurological symptoms

commonly observed in Rett syndrome, such as global

shrinkage of the brain, increased neuronal cell density,

retraction of dendritic arbors, reduction of synaptic proteins

and altered astrocytic development, among others (Nguyen

et al. 2012). This is further evidence of the involvement of

MeCP2 in regression from a normal mature brain to a Rett-

like brain. This dynamism is of vital importance and sug-

gests opportunities for reverting the Rett phenotype. In this

regard, Rett syndrome is not a neurodegenerative disorder,

neurons do not die, opening the opportunities of phenotypic

reversion by means of MeCP2 restoration (Giacometti et al.

2007; Guy et al. 2007; Tropea et al. 2009).

MeCP2 protein is widely expressed in several tissues but

the highest level of expression has been observed in the

brain (Zachariah and Rastegar 2012). Although a higher

level of MeCP2 expression has been described in neurons,

especially in postmitotic neurons, deregulation of MeCP2

expression in glia cells also contributes to the progression

of Rett syndrome (Ballas et al. 2009). MeCP2 was initially

identified as a transcriptional repressor that binds to

methylated CpG dinucleotides and recruits corepressors

such as mSin3 and HDACs (Jones et al. 1998). However, in

recent years, studies have concluded that MeCP2 may act

either as a repressor or an activator, depending on its

interaction proteins (Chahrour et al. 2008; Yasui et al.

2007). Chahrour et al. (2008) examined the gene expres-

sion profiles in the hypothalamus of mice lacking or

overexpressing MeCP2 and, contrary to expectation, con-

firmed that MeCP2 occupancy preferentially occurs in

active genes (85 %) and is associated with binding to the

transcriptional activator CREB1. In accordance with this

finding, similar genome-wide analyses of MeCP2 binding,

CpG methylation and gene expression showed that MeCP2

binds methylated and unmethylated DNA preferentially to

actively expressed genes (Yasui et al. 2007). Several

MeCP2 target genes (UBE3A, DLX5, BDNF and PRODH)

have been identified (Samaco et al. 2005; Horike et al.

2005; Chang et al. 2006; Urdinguio et al. 2008), although

no direct link between MeCP2-dependent expression of

these genes and the phenotypic abnormality of Rett syn-

drome has so far been found. A role for oxidative stress as

a mechanism underlying the Rett phenotype has been

suggested (De Felice et al. 2012) mainly on the basis of

two observations: (i) oxidation of either a single guanine to

8-oxoG or of a single 5mC to 5hmC, significantly inhibits

(by at least an order of magnitude) binding of MeCP2 to

the oligonucleotide duplex (Valinluck et al. 2004); (ii)

several MeCP2 target genes affect the oxidative stress

response, such as BDNF, CREB or Prodh (Chang et al.

2006; Urdinguio et al. 2008). Finally, analysis of the

posttranslational modifications of MeCP2 proteins could

also provide insight into the effect on synaptic plasticity

mediated by the regulation of specific genes. Recent work

has shown that phosphorylation of MeCP2 at serine 421 is

induced by membrane depolarization and leads to the

regulation of BDNF transcription (Zhou et al. 2006).

Interestingly, a mouse model showed that phosphorylation

at serine 421 has widespread effects on synaptic plasticity

(Li et al. 2011). Neuronal activity also influences dephos-

phorylation of MeCP2 at serine 80, which alters the tran-

scription of several genes (Tao et al. 2009). Considering

these results together suggests that further research is

warranted into the role of these MeCP2 posttranslational

modifications (and other phosphorylation sites) in neuronal

plasticity. It should be stressed that recent evidence sug-

gests that MeCP2 is not only involved in transcriptional

regulation, but also possibly in RNA splicing (Young et al.

2005), chromatin condensation (similar to H1 function)

(Ishibashi et al. 2008) and the silencing of repetitive ele-

ments (Muotri et al. 2010). These findings demonstrate that

MeCP2 function and its involvement in Rett syndrome

might be more complex than previously appreciated.

Finally, MeCP2 mutations are also linked to a broad

spectrum of neurological disorders (Van Esch et al. 2005;

Villard 2007), and to autism (Carney et al. 2003), Angel-

man syndrome (Watson et al. 2001) and Prader–Willi

syndrome (Samaco et al. 2004). As mentioned before,

duplications or triplications on chromosome Xq28 con-

taining the MeCp2 region are also associated with the Lubs

X-linked mental retardation syndrome (Van Esch et al.

2005). Taking together, it must be highlighted that both

down- and overexpression of MeCP2 result in altered

neuron function, an aspect that must be especially con-

sidered for therapeutic purposes based on MeCP2 restora-

tion. Although it is clear that MeCP2 deficiency affects the

brain function, a definitive molecular pathology of the

MeCP2-associated disorders remains elusive. In this con-

cern, progresses are currently being carried out mainly due

to the development of appropriate experimental systems,

such as stem cell-based system allowing the synchronous

differentiation of neuronal progenitors in wild-type or

mutant MeCP2 (Yazdani et al. 2010) or by the develop-

ment of several mouse models that reproduce many traits

of Rett syndrome (Na et al. 2012). Hopefully their findings

will help us better understand the many facets of the

pathobiology of the disease.

Genetic alteration of histone modifiers

The histone modification network is very complex.

Post-transcriptional histone modifications can occur in

various histone proteins (e.g., H2B, H3, H4) and variants

364 Hum Genet (2013) 132:359–383

123

(e.g., H3.3) and affect different histone residues (lysine,

arginine, serine) located in their N-terminal tails (Esteller

2008; Bannister and Kouzarides 2011). Several chemical

groups [methyl, acetyl, phosphate, small ubiquitin-related

modifier (SUMO) and ADP-ribose] may be added in dif-

ferent degrees depending on the chemical modification

(mono-, di- or trimethylation) (Bannister and Kouzarides

2011). Cross-talk between histone marks can occur within

the same residue, in the same tail or among different his-

tone tails (Portela and Esteller 2010) and, as a conse-

quence, the functional significance of histone modifications

depends on the combination of all marks (the ‘‘histone

code’’). Furthermore, we must not forget that an additional

level of complexity exists due to the communication

between the epigenetic marks involving DNA, histone and

chromatin-related proteins. Histone modifications are

involved in gene transcription, although the consequence of

each mark depends on the residue affected and the type of

modification. In general, acetylation of lysines is associated

with transcriptional activation. However, methylation of

lysine 4 of the H3 histone is associated with active tran-

scription whereas methylation of lysines 9 and 27 is

associated with gene silencing (Bannister and Kouzarides

2011). Gene transcription is not the only characteristic that

is controlled in this way; histone modifications are a

mechanism for controlling chromatin structure and they

also affect more global biological processes such as DNA

repair, DNA replication, alternative splicing and chromo-

some condensation (Portela and Esteller 2010).

Addition of chemical groups to histone residues is a very

dynamic and reversible process catalyzed by two sets of

enzymes (and their protein complexes) that have antago-

nistic activities, enzymes that covalently attach the chem-

ical groups and others for removing them (Fig. 1).

Acetyltransferases (HATs) and histone deacetylases

(HDACs) are among the least specific histone modifiers

because they are able to modify several residues. Con-

versely, histone methyltransferases (HMTs), histone

demethylases (HDMTs) and kinases have higher specificity

(Portela and Esteller 2010). Genetic alterations of histone

modifier enzymes are frequently linked to human diseases.

In this regard, aberrations in the histone modification

profiles associated with cancer could be a consequence of

the genetic disruption of the epigenetic machinery

Normal development

…K… DRLVKRHRKAGGKGLGKGGKGRGS91 135812161820

- N- terminal

P PMeAcAc

Ac

MeAc

Ac

Me

CBP

P300

pCAFSWI/SNF

DNMT3B

PRMT1

CARM1

HDAC1HDAC2

SINA3MeCP2

CH3

H4

Pri-mRNA

Pre-mRNA

DroshaXPO5/mRNA

DICER

miRNA

RISC

Genetic alterations of epigenetic genes

Writers

Ac

Me

P

5mC DNMTs

HATs

HMTs

Kinases

Readers

Ac

Me

Bromodomains

ChromodomainsPHD domainsPWWP domainsTudor domains

5mC MBDs

Erasers

Ac

Me

P

HDACs

HDMTs

Phosphatases

Epigenetic therapies

HDAC inhibitorsHDMT inhibitors

DNA demethylating agentsOthers

miRNA

Fig. 1 Epigenetic mechanisms disrupted in human disorders. Epige-

netic mechanisms regulate chromatin function and cell identity.

Appropriate activity of enzymes controlling DNA methylation,

histone modifications and non-coding RNAs controls the temporal

and spatial patterns of gene expression, DNA repair and DNA

replication. Their deregulation may contribute to human diseases.

Epigenetic-based therapies, such as histone deacetylase inhibitors, can

partially alter the phenotype of the disease by recovering the aberrant

epigenetic patterns, and are a promising area in pharmacological

research. Chemical modifications at histone H4 are shown as a

representative example of histone marks. 5-mC; 5-methylcytosine; Achistone acetylation, DNMTs DNA methyltransferases, HATs histone

acetyltransferases, HDACs histone deacetylases, HDMTs histone

demethylases, HMTs histone methyltransferases, MBDs methyl-

binding domain proteins, Me histone methylation, P histone phos-

phorylation, PHD plant homeodomain, PWWP proline–tryptophan–

tryptophan–proline domain, XPO5 exportin-5

Hum Genet (2013) 132:359–383 365

123

(Berdasco and Esteller 2010). Several hematological

malignancies can be associated with chromosomal trans-

locations in the coding region of HATs (i.e., CBP-MOZ) or

HMTs (i.e., mixed-lineage leukemia 1 (MLL1), or nuclear

receptor binding SET domain protein 1 (NSD1). In solid

tumors, both HMT genes [such as EZH2, mixed-lineage

leukemia 2 (MLL2)] and DNMTs [i.e., Jumonji domain-

containing protein 2C (JMJD2C/GASC1)] are known to be

amplified (Berdasco and Esteller 2010). In this section we

will focus on non-tumoral human diseases in which the

epigenetic profile changes as a consequence of genetic

alterations in histone modifiers (Table 1).

MYST4 acetyltransferase (KAT6B) mutations

in Genitopatellar syndrome and Say-Barber-Biesecker-

Young-Simpson syndrome

Genitopatellar syndrome (GPS, MIM #606170) is a rare

skeletal dysplasia consisting of microcephaly, severe psy-

chomotor retardation and craniofacial defects, associated

with congenital flexion contractures of the lower extremi-

ties, abnormal or missing patellae, and urogenital anoma-

lies (Reardon 2002). To date it has been described in only

18 subjects (Campeau et al. 2012a). Whole-exome

sequencing identified mutations in the KAT6B acetyl-

transferase that lead to protein truncation (Campeau et al.

2012a; Simpson et al. 2012). All mutations are heterozy-

gous, exhibit autosomal dominant inheritance and occur in

the proximal portion of the last exon (Campeau et al.

2012a). KAT6B is a member of the MYST family of

proteins containing a conserved acetyltransferase domain

(Champagne et al. 1999). The absence of decreased

expression of the KAT6B transcript has been described in

GPS patients (Campeau et al. 2012a); however, GPS sub-

jects were characterized by decreased global acetylation of

histone H3 and H4 (Simpson et al. 2012).

Heterozygous mutations of KAT6B have also been

described in patients with Say-Barber-Biesecker-Young-

Simpson syndrome (SBBYS, MIM #603736) (Clayton-

Smith et al. 2011). The main clinical features associated

with the syndrome are distinctive facial appearance, severe

hypotonia and feeding problems, associated skeletal prob-

lems, cardiac defects, severe intellectual disability, delayed

motor milestones, and significantly impaired speech

(Clayton-Smith et al. 2011). Unlike with GPS syndrome,

mutations in SBBYS patients are located throughout the

gene or more distally in the last exon. Although GPS and

SBBYS share several clinical features, such as severe

intellectual disability, cardiac defects and genital abnor-

malities, the range of phenotypic alteration varies between

the two syndromes (Campeau et al. 2012b). Campeau and

collaborators created a database for establishing correla-

tions between phenotype and genotype in patients carrying

KAT6B mutations. Their preliminary results suggested that

the common features are a consequence of haploinsuffi-

ciency of the C-terminal region, whereas the unique phe-

notypes of GPS could arise from the expression of a

truncated protein that acquires new cellular functions

(Campeau et al. 2012b).

The molecular mechanisms of abrogation of KAT6B

function that lead to defective neural development are

not currently known. The Querkopf mouse model that

only expressed a 5 % of the MYST4 levels quantified for

wild-type mice leads to a phenotype commonly observed

in human syndromes: brain development defects, facial

dysmorphisms and alteration of bone growth (Thomas

et al. 2000), supporting the role of KAT6B in cerebral

cortex development. According to this idea, KAT6B is

expressed in developing cerebral cortex, adult neural

stem cells, osteoblasts and germ cells (Merson et al.

2006). A study performed in one Noonan-like phenotype

patient, with a chromosomal breakpoint in KAT6B

resulting in 50 % gene expression, and in Querkopf mice,

described a reduction of H3 acetylation that specifically

dysregulates the expression of genes in the MAPK

pathway (Kraft et al. 2011).

Genetic disruption of ep300/CBP acetyltransferases

in Rubinstein–Taybi syndrome

The Rubinstein–Taybi syndrome (RSTS, MIM #180849) is

a well-defined disease characterized by postnatal growth

deficiency, microcephaly, specific facial characteristics,

broad thumbs, big toes and intellectual disability. An

increased risk of tumors (mainly leukemia in childhood and

meningioma in adulthood) has been observed (Hennekam

2006). Although the exact molecular etiology of RSTS is

not clearly understood, it is widely accepted that RSTS is

associated with breakpoints, translocations, mutations and

microdeletions of chromosome 16p13.3 (Lacombe et al.

1992). Petrij et al. (1995) were the first to report that

mutations in the gene encoding the CREB binding protein

(CBP), located in the aforementioned region, could cause

RSTS. Recent investigations employing larger series of

RSTS samples detected CBP mutations in 45–55 % of

patients (Roelfsema et al. 2005; Tsai et al. 2011).

Furthermore, CBP has a homolog located at 22q13.2,

known as the E1A-binding protein p300 (p300) (Arany

et al. 1994). The exact frequency of genetic alterations of

p300 in RTS is not yet known, but some sources estimate it

to be 3 % (Bartholdi et al. 2007; Bartsch et al. 2010). Since

a cytogenetic or molecular abnormality in p300/CBP could

be detected in about 55 % of patients, further work to

explain the cause of the syndrome in the remaining 45 % of

patients without a ‘‘classic’’ genetic abnormality is still

needed.

366 Hum Genet (2013) 132:359–383

123

CREB binding protein was first identified as a nuclear

transcription coactivator that binds specifically to CREB

when it is phosphorylated (Chrivia et al. 1993), while p300

was originally described by protein-interaction assays with

the adenoviral E1A oncoprotein (Eckner et al. 1994).

Although both proteins are highly homologous (63 %

homology at the amino acid level) and have common

interaction partners, they have distinct cellular functions

and cannot always replace one another (Viosca et al. 2010).

There are two biological mechanisms whereby defects in

p300/CBP function could cause the RTS symptoms:

(i) CBP and p300 proteins act as cofactors for over 300

transcriptional factors, including several regulators

involved in neuronal activity, such as c-Fos, c-Jun, CREB

or NF-jß, known oncoproteins (myb), transforming viral

proteins (E1A, E6, large T antigen) and tumor-suppressor

proteins (p53, E2F, RB, Smads, RUNX, BRCA1) (Chan

and La Thangue 2001; Kasper et al. 2011); (ii) both pro-

teins have HAT activity that targets the N-terminal tails of

histones and contributes to transcriptional activation by

relaxing the structure of the nucleosomes (Ogryzko et al.

1996). CBP and ep300 have some common activities, such

as the acetylation of H4K5, H3K14, H3K18, H3K27 and

H3K56 (Das et al. 2009; Jin et al. 2011). However, they

also have unique properties such as substrate specificity

profiles that could explain functional differences of both

enzymes (McManus and Hendzel 2003). RSTS disorder

has been modeled in mice, and several heterozygous

cbp ± mice (homozygous cbp -/- mutants are embryonic

lethal) have been generated (Bourtchouladze et al. 2003;

Alarcon et al. 2004). These model animals exhibit deficits

in long-term memory and cognitive impairments reminis-

cent of human RSTS neural symptoms, confirming the role

of CBP in the etiology of the disease (Alarcon et al. 2004;

Korzus et al. 2004). At the molecular level, these mice

have reduced HAT activity, decreased acetylation of spe-

cific histone proteins and impaired CBP-dependent gene

expression (Alarcon et al. 2004; Korzus et al. 2004). The

role of CBP in neural differentiation and development has

been recently demonstrated in CBP genetically modified

models (Wang et al. 2010). Phosphorylation of CBP by

atypical protein kinase C f is necessary for CBP binding to

neural promoters, followed by histone acetylation and

transcriptional activation, leading to neural differentiation

of stem cell precursors (Wang et al. 2010). This mechanism

could explain how CBP alterations can result in cognitive

dysfunction of RSTS patients.

HDAC4 histone deacetylase mutations

in Brachydactyly-mental retardation syndrome

Brachydactyly-mental retardation syndrome (BDMR, MIM

#600430) is a complex disease that presents a wide

spectrum of clinical features, such as intellectual disabilities,

developmental delays, sleep disturbance, craniofacial and

skeletal abnormalities (including brachydactyly type E),

cardiac defects and autism (Aldred et al. 2004). Hetero-

zygous mutations in the HDAC4 deacetylase gene located

on chromosome 2q37.2 have been reported in BMRS

subjects (Williams et al. 2010; Morris et al. 2012). HDAC4

acts as a corepressor for transcription factors regulating the

expression of genes from the osteogenic, chondrogenic,

myogenic and neurogenic differentiation pathways (Miska

et al. 2001; Arnold et al. 2007; Chen and Cepko 2009).

HDAC4 is essential for the repression of RUNX2 and

MEF2 transcription factors in normal bone development

(Arnold et al. 2007). Indeed, mice with a deleted MEFC2

gene have impaired chondrogenic and osteogenic devel-

opment that antagonizes the phenotype of the Hdac4

mutant mice, which is similar to the human BDMR phe-

notype (Arnold et al. 2007; Rajan et al. 2009). These

results suggest that haploinsufficiency of HDAC4 causes

BDMR through its ability to regulate important master

genes of cellular differentiation.

Mutations in histone methyltransferase EHMT1

in Kleefstra syndrome

Kleefstra syndrome (MIM #610253), previously known as

9q subtelomeric deletion syndrome, is characterized

by severe intellectual disability, hypotonia, brachy(micro)

cephaly, epileptic seizures, flat face with hypertelorism,

synophrys, anteverted nares, everted lower lip, carp mouth

with macroglossia, and heart defects (Willemsen et al.

2012). The mutational landscape of Kleefstra patients

includes a microdeletion in the distal long arm of chro-

mosome 9q or intragenic loss of function mutations in the

histone methyltransferase EHMT1 (Kleefstra et al. 2006,

2009), both leading to haploinsufficiency of EHMT1.

EHMT1 is a specific HMT for lysine 9 at histone H3 and is

involved in gene repression (i.e., the NF-kB gene) (Ogawa

et al. 2002; Ea et al. 2012). It has not been established how

EHMT1 disruption results in the phenotypic skills of

Kleefstra syndrome, but recent research on EHMT mutants

in Drosophila melanogaster demonstrates that learning and

memory defects could be restored after re-expression of

EHMT (Kramer et al. 2011). Interestingly, the same

authors have recently identified new genetic mutations

affecting epigenetic modifiers in Kleefstra syndrome sub-

jects without mutations in the EHMT1 gene, including the

methyl-binding domain MBD5, the histone methyltrans-

ferase MLL3 or the chromatin-remodeling factor

SMARCB1 (Kleefstra et al. 2012). These findings highlight

the crucial role of epigenetic modifiers in brain develop-

ment and strongly emphasize the need to explore this area

of research further.

Hum Genet (2013) 132:359–383 367

123

NSD1 histone methyltransferase genetic alterations

in Sotos syndrome

Sotos syndrome (MIM #117550) is an autosomal dominant

condition characterized by overgrowth that results in tall

stature and macrocephaly, a distinctive facial appearance,

learning disability (Lapunzina 2005; Tatton-Brown and

Rahman 2007), and an increased incidence of malignant

neoplasms (Rahman 2005). The distinctive head shape and

size has led to Sotos syndrome sometimes being called

cerebral gigantism (Tatton-Brown and Rahman 2007).

Most cases of NSD1 mutational mechanisms, including

truncating, missense and splice-site mutations and

deletions, result in loss of function of the NSD1 protein

(Tatton-Brown and Rahman 2007). Mutations in the

nuclear receptor SET domain containing protein-1 gene

(NSD1), which encodes a histone methyltransferase of

lysine residues H3K36 and H4-K20, are found in patients

exhibiting the clinical symptoms of Sotos syndrome

(Kurotaki et al. 2002; Rayasam et al. 2003). Recently,

mutations in the NFIX gene were associated with a Sotos

syndrome-like phenotype without NSD1 mutations (Yon-

eda et al. 2012).

NSD1 is essential for early postimplantation of embryos

and NSD1 homozygous mutants are embryonic lethal,

although heterozygous mutant NSD1 are viable and fertile

(Rayasam et al. 2003). The NSD1 protein contains a

su(var)3-9, enhancer-of-zeste, trithorax (SET) domain

responsible for HMT activity and other functional domains,

including plant homeodomain (PHD) and proline–trypto-

phan–tryptophan–proline (PWWP) domains, both of which

are involved in a protein–protein interaction (Kurotaki

et al. 2001). Additionally, the potential of NSD1 to mono-

and dimethylate lysines K218 and K221 of the p65 subunit

of the immune response gene NF-kB has been noted (Lu

et al. 2010). NSD1 has previously been shown to interact

with nuclear receptors, such as Nizp1, a DNA-binding

transcriptional repressor (Huang et al. 1998; Nielsen et al.

2004), but to date there has been no evidence clarifying

whether NSD1 mutations contribute to deregulation of

brain function. It has become clear that NSD1 is a versatile

protein that can act as a corepressor or coactivator,

depending on the cellular context (Huang et al. 1998;

Pasillas et al. 2011). According to this idea, binding of

NSD1 PHD domains to target genes is guided by the

presence of specific histone marks of promoters (Pasillas

et al. 2011), specifically methylation at lysine H3K4 and

H3K9. By binding to trimethylated H3K9, NSD1 can

recognize genes that are transcriptionally repressed and

interact with other repression complexes (i.e., DNMT1 or

HP1), whereas its interaction with trimethylated H3K4

allows binding to active genes (Pasillas et al. 2011). In

addition, patients with genetic disruption of the NSD1 gene

have an increased risk of developing malignancy before

adulthood, including neuroblastoma, Wilms tumors and

hematological malignancies (Rahman 2005). NSD1 also

has a tumor-suppressor function (Berdasco et al. 2009).

NSD1 function is abrogated in neuroblastoma and glioma

cells by transcriptional silencing associated with CpG

island-promoter hypermethylation, and restoration of its

expression demonstrates that its tumor-suppressor features

are mediated by a mechanism dependent on MEIS1

expression (Berdasco et al. 2009).

Finally, occasional individuals have NSD1 defects that

overlap clinically with Sotos syndrome and other condi-

tions, such as Weaver syndrome 1 (WVS1, MIM #277590)

(Douglas et al. 2003). Beckwith–Wiedemann syndrome

(BWS, MIM #130650) is, like Sotos syndrome, an over-

growth syndrome. It is cause by deregulation of imprinted

growth-regulatory genes within the 11p15 region. Inter-

estingly, correlations between the two syndromes have

been found: first, unexplained Beckwith–Wiedemann

patients could be related to NSD1 deletions or mutations

(2/52 cases) and secondly, 11p15 anomalies (including the

KCNQ10T1 imprinting center) were identified in Sotos

syndrome cases (2/52) (Baujat et al. 2004; Mayo et al.

2012). A potential role for NSD1 in imprinting of the

11p15 region is suggested, although the molecular basis for

this association is not known.

EZH2 histone methyltransferase mutations

and Weaver syndrome

Weaver syndrome 2 (WVS2, MIM #614421) is an over-

growth syndrome characterized by tall stature, advanced

bone age, macrocephaly, hypertelorism, learning disabili-

ties and dysmorphic facial features (Weaver et al. 1974). A

predisposition to hematological malignancies has also been

reported (Basel-Vanagaite 2010). Heterozygous mutations

in the histone methyltransferase EZH2 gene on chromo-

some 7q36.1 have been identified in Weaver syndrome

patients (Gibson et al. 2012). EZH2 protein is a member of

the polycomb repressive complex 2 (PRC2), together with

SUZ12 and EED, which catalyses the trimethylation of

lysine H3K27 (Kirmizis et al. 2004). Mammalian EZH2

has critical roles in X-chromosome inactivations, genomic

imprinting during germline development, stem cell main-

tenance and cell lineage determination, including osteo-

genesis, myogenesis and hematogenesis (Chou et al. 2011;

Wyngaarden et al. 2011). A role for EZH2 in regulating the

circadian-clock functions has been suggested (Etchegaray

et al. 2006). In addition, mice with targeted mutant EZH2

beta cells have reduced beta cell proliferation and beta cell

mass (Chen et al. 2009), whereas mice with EZH2 mutant

satellite cells exhibit defects in muscle regeneration (Juan

et al. 2011). Some characteristics of these phenotypes are

368 Hum Genet (2013) 132:359–383

123

shared with that of human Weaver syndrome, such as

defects in limb development (Wyngaarden et al. 2011).

However, to date, few studies have provided any insight into

the specific contribution of EZH2 mutations in the Weaver

phenotype. As described above, some patients with Weaver

syndrome have a mutated NSD1 gene that is responsible for

the overgrowth Sotos syndrome (Douglas et al. 2003). There

are some clinical features common to both syndromes (i.e.,

developmental delay, overgrowth and macrocephaly), but

some features are specific to Weaver syndrome 2 (i.e., ret-

rognathia with a prominent chin crease or carpal bone age)

(Gibson et al. 2012). Indeed, EZH2 protein acts in the PI3K/

mTOR pathway, which has been associated with growth

defects. This suggests that the pathways through NSD1 and

EZH2 HTMs that contribute to overgrowth disorders can be

different (Tatton-Brown et al. 2011).

Histone methyltransferase (MLL2) and demethylase

(JMJD3) mutations in Kabuki syndrome

Kabuki syndrome 1 (MIM #147920) is an autosomal

dominant intellectual disability syndrome with additional

features, including a highly distinctive recognizable facial

phenotype characterized by long palpebral fissures with

eversion of the lateral third of the lower eyelids, a broad

and depressed nasal tip, large prominent earlobes, scoliosis,

short fifth finger, persistence of fingerpads, radiographic

abnormalities of the vertebrae, hands, and hip joints, and

others (Niikawa et al. 1981). Mutations in the histone

methyltransferase MLL2 gene are a major cause of Kabuki

syndrome (type 1) (Ng et al. 2010; Hannibal et al. 2011),

but mutations in the histone demethylase KDM6A have

also been found in Kabuki syndrome (type 2, MIM

#300867) (Lederer et al. 2012). MLL2 is a lysine H3K4-

specific histone methyltransferase that belongs to the SET1

family of proteins (Dillon et al. 2005), whereas KDM6A

(JMJD3) is a histone demethylase that specifically acts in

mono- di- and trimethylated lysine H3K27 (Hong et al.

2007; Lan et al. 2007). Both enzymes help regulate genes

from the myogenic lineage during embryogenesis (Aziz

et al. 2010; Seenundun et al. 2010). The identification of

mutations in MLL2 and KDM6A suggests a crucial effect

of altered histone methylation profiles on the phenotype of

Kabuki syndrome.

Histone demethylase PHF8 mutations in Siderius

X-linked mental retardation syndrome

Siderius X-linked mental retardation syndrome (MRXSSD,

MIM #300263) is an inherited condition that was first

described in 1999 as a heterogeneous intellectual disability

syndrome associated with cleft lip/cleft palate (Siderius

et al. 1999). Mutations in the PHD finger protein 8 (PHF8)

gene located on the Xp11 chromosome have been identi-

fied in subjects with MRXSSD (Laumonnier et al. 2005;

Abidi et al. 2007; Koivisto et al. 2007). The PHF8 protein

contains a PHD-type domain zinc finger domain and a

Jumanji domain, the latter conferring histone demethylat-

ing catalytic activity with specificity for: mono- and

dimethylated histone H3 at lysine K9 (Yu et al. 2010) and

mono-methyl histone H4 at lysine K20 (Qi et al. 2010).

PHF8 transcript is strongly expressed in the embryonic and

early postnatal steps of brain development (Laumonnier

et al. 2005), implying a connection between PHF8 muta-

tions and the MRXSSD phenotype. Some evidences of the

functional role of PHF8 in different experimental models

exist (Liu et al. 2010; Qi et al. 2010). In zebrafish, it has

been described that PHF8 regulates brain apoptosis and

craniofacial development through the transcriptional gene

regulation (Qi et al. 2010); in Caenorhabditis elegans, a

RNA interference-based functional genomic project iden-

tified PHF8 as a gene involved in controlling cellular

growth and differentiation during embyogenesis (Fernan-

dez et al. 2005); in human HeLa cells, PHF8 deficiency by

siRNA mechanisms leads to a delay in G1/S transition and

its dissociation from chromatin in early mitosis which

demonstrates an active role of PHF8 in the control of cell

cycle (Liu et al. 2010). Interestingly, PHF8 interacts with

another MRXSSD protein, the transcription factor ZNF711

(Kleine-Kohlbrecher et al. 2010). PHF8 and ZNF11 pro-

teins share a set of target genes, being of special relevance

the interaction of both proteins with JARID1C (KDM5C)

(also involved in alterations of the intelectual ability)

(Kleine-Kohlbrecher et al. 2010; Claes et al. 2000). In

addition to MRXSSD syndrome, defects affecting the

chromosomal region of PHF8 (a larger Xp11.22 deletion

that includes the FAM120C and WNK3 genes) have also

been associated with autism (Qiao et al. 2008).

Histone demethylase JARID1C (KDM5C) mutations

in Claes-Jensen X-linked mental retardation syndrome

Mutations in the histone demethylase JARID1C (KDM5C)

were first identified in individuals with X-linked mental

retardation syndrome with additional features of progres-

sive spastic paraplegia, facial hypotonia, aggressive

behavior and strabismus (MIM #300534) (Claes et al.

2000; Jensen et al. 2005). Heterogeneous clinical features

associated with XLMR and mutated KDM5C have been

consistently identified since then (Abidi et al. 2008; Santos-

Reboucas et al. 2011; Ounap et al. 2012). KDM5C gene

encodes a specific histone H3 demethylase at lysine K4

(Tahiliani et al. 2007). It is ubiquitously expressed

although fetal brain tissues have higher KDM5C expres-

sion levels than other tissues (Xu et al. 2008). The tran-

scriptional repressor activity of KDM5C is mediated by the

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123

Re-1 silencing transcription factor (REST) complex

(Tahiliani et al. 2007). Interestingly, knock-out of the

KDM5C complex results in increased trimethylation at

H3K4 and gain of expression of SCN2A and SYN1 neuro-

logical genes, and provides evidence of the contribution of

KDM5C complex to X-linked mental retardation defects

(Tahiliani et al. 2007).

Mutations in chromatin remodelers

Nucleosome positioning and, consequently, DNA accessi-

bility may be controlled by mechanisms that are indepen-

dent of histone-modifying enzymes. Several groups of

protein complexes (‘‘chromatin-remodeling complexes’’)

are known to restructure nucleosomes in an ATP hydro-

lysis-dependent manner. To date, four families of chro-

matin remodelers have been described in eukaryotes: SWI/

SNF, ISWI, NURD/Mi-2/CHD, and INO80/SWR1 (Har-

greaves and Crabtree 2011). The ATPase domain is a

common feature, but the composition of the different

subunits comprising the complex is highly variable. In a

similar manner, each ATPase domain may be targeted to

specific domains (i.e., bromodomain, DNA helicase, etc.).

Together, the binding affinity and the complex composition

confer unique features on chromatin remodelers in a wide

range of biological processes and genomic contexts.

SWI/SNF is one of the best studied chromatin-remod-

eling complexes in human cells and is composed of at least

15–20 subunits, including ATPases, catalytic subunits (i.e.,

SMARCA2 and SMARCA4) and structural components

involved in target recognition or stabilization functions

(i.e., ARID1A, ARID1B and SMARCC1) (Hargreaves and

Crabtree 2011). All members of this complex contain either

SMARCA2 (also known as Brahma protein) or SMARCA4

(also known as BRG1) as a catalytic unit. The two proteins

share 75 % amino acid homology (Santen et al. 2012). The

SWI/SNF complex plays a crucial role in cell differentia-

tion (Ho et al. 2009), cell cycle (Nagl et al. 2007) and DNA

repair (Park et al. 2006). In the human ISWI (imitation

switch) family of chromatin remodelers, the catalytic sub-

unit is represented by SNF2H and SNF2L proteins (Flaus

and Owen-Hughes 2011). ISWI complexes participate in

biological functions such as chromatin assembly, nucleo-

some spacing, DNA replication and activation or repres-

sion of transcriptional regulation (Erdel and Rippe 2011).

The CHD family also contains a SNF2L ATPase domain

together with tandem chromodomains in the N-terminal

region (Murawska and Brehm 2011). CHD complexes are

highly versatile and although they are involved in tran-

scriptional regulation, various CHD regulatory complexes

are involved in the initiation, elongation or termination of

transcription. Furthermore, specific CHD complexes, such

as Mi-2/nuRD, contain HDAC and MBD proteins in the

same complex (Murawska and Brehm 2011). The INO80

subfamily is the most recently identified SWI/SNF family

of chromatin remodelers. Mammalian INO80 complex

comprises the INO80 catalytic unit and Snf2-related CBP

activator protein (SRCAP) and p400 subunits (Morrison

and Shen 2009). The INO80 subfamily is the most evolu-

tionarily conserved of all the chromatin-remodeling com-

plexes due to the high degree of homology of its ATPase

subunit (Morrison and Shen 2009). Apart from regulation

of transcription, the INO80 complex is involved in genome

stability pathways, such as DNA repair, replication, telo-

mere regulation and centromere stability (Ho and Crabtree

2010). In summary, ATP-dependent enzymes that remodel

chromatin are important regulators of chromatin dyna-

mism. Evidence is emerging that alterations in such chro-

matin-remodeling complexes have consequences for

normal development. Some examples of genetic mutations

of chromatin-remodeling complexes in human diseases are

summarized in this section (Table 1).

ATXN7 mutation in Spinocerebellar Ataxia 7

Spinocerebellar Ataxia Type 7 (SCA7; MIM 164500) is an

autosomal dominant inherited neurodegenerative disorder

characterized by progressive cerebellar ataxia, including

dysarthria and dysphagia, and cone-rod and retinal dys-

trophy with progressive central visual loss resulting in

blindness in affected adults. The disease is caused by an

expanded CAG trinucleotide repeat encoding a polygluta-

mine tract in ataxin-7 (ATXN7) gene, from 4 to 35 repeats

in normal gene to a variable expansion of 36–306 repeats in

pathogenic ATXN7 variants (Garden and La Spada 2008).

ATXN7 protein is a transcription factor with important

roles in chromatin regulation through its effect on histone

modification and histone deubiquitination. It is a member

of the transcription coactivator complex STAGA (SPT3/

TAF9/GCN5) with acetyltransferase activity, but may also

be found in the USP22 deubiquitination complex (Sopher

et al. 2011). Although the nuclear expression of ATXN7 is

necessary for transcriptional regulation, a functional role

for cytoplasmic ATXN7 in the regulation of cytoskeletal

dynamics (mediated by its interaction with microtubules)

has recently been proposed (Nakamura et al. 2012).

Defects of the nuclear ATXN7 gene have been correlated

with the SCA7 phenotype (Chen et al. 2012a, b), although

the molecular mechanisms underlying the disease are not

clearly understood and the effect of epigenetic dysregula-

tion of target genes is still a matter of debate. Some results

from yeast and mice indicate that loss of the Gcn5 ace-

tyltransferase function triggered by polyQ-Atxn7, resulting

in chromatin structure changes, could be involved in the

SCA7 phenotype (Yoo et al. 2003; McMahon et al. 2005;

370 Hum Genet (2013) 132:359–383

123

Helmlinger et al. 2006). In contrast, loss of Gcn5 functions

in mice bearing polyQ-Atxn7 accelerates neuronal dys-

function in a mechanism that is independent of gene

expression changes (Chen et al. 2012a, b). Deciphering the

exact causal consequences of ATXN7 dysregulation in

SCA7 disease through its role as nuclear transcription

regulator or cytoplasmic function will need further

research.

ATRX mutations in alpha-thalassemia X-linked mental

retardation syndrome

ATR-X syndrome (MIM #301040) is an X-linked disorder

comprising severe psychomotor retardation, characteristic

facial features, genital abnormalities, and the blood disease

alpha-thalassemia (Gibbons et al. 1995). Mutations in the

ATRX gene located at Xq21.1 and coding for a member of

the SWI/SNF chromatin-remodeling family of proteins

underpin the molecular genetics of the disease (Gibbons

et al. 1995). The X-linked mental retardation-hypotonic

facies syndrome (MIM #309580) and the alpha-thalassemia

myelodysplasia syndrome (MIM #300448) are also asso-

ciated with mutations in the ATRX gene (Abidi et al. 2005;

Gibbons et al. 2003). The N-terminus contains a globular

domain, called ADD (ATRX-DNMT3-DNMT3L) that can

bind to the N-terminal of histone H3 (Argentaro et al.

2007). Indeed, ATRX is known to be required for the

incorporation of the histone H3.3 specifically at telomeric

sequences (Lewis et al. 2010). On the other hand, the

C-terminus contains seven helicase/ATPase domains that

share sequence homology with the SNF2 family of proteins

(Picketts et al. 1996). Through this domain, ATRX shows

in vitro ATP-dependent nucleosome remodeling and DNA

translocase activities (Gibbons et al. 2003). The ATRX

protein is expressed genome-wide, but is enriched at telo-

meric and subtelomeric regions (Law et al. 2010). In this

context, decreased ATRX expression is associated with

altered expression of telomere-associated RNA (Goldberg

et al. 2010) and the DNA-damage response during S-phase

at telomeric regions of pluripotent stem cells (Wong et al.

2010). The mechanisms by which ATRX is recruited to

telomeric regions are not fully understood, although ATRX

binding depends on trimethylation at K9H3 (Kourmouli

et al. 2005). It binds to tandem repeat sequences with

G-rich motifs and has been predicted to form non-B DNA

structures (Law et al. 2010). More importantly, the size of

the tandem repeats located in specific genes influences their

expression (Law et al. 2010), providing a molecular

explanation of how the same mutation at the ATRX gene

can result in different phenotypes. Furthermore, ATRX

mutations have been correlated with alterations in the DNA

methylation patterns of highly repeated sequences,

including rDNA, Y-specific satellite and subtelomeric

repeats (Gibbons et al. 2000). The interplay between

ATRX and the DNA methylation machinery is reinforced

by the discovery that the methyl-binding domain protein

MECP2 targeted the C-terminal helicase domain of ATRX

to heterochromatic foci (Nan et al. 2007). MeCP2 is also

mutated in Rett syndrome, so the finding suggests that

alteration of the MECP2–ATRX interaction leads to path-

ological changes that contribute to the intellectual dis-

ability phenotype observed in both syndromes.

Mutations in ERCC6 and Cockayne syndrome

Cockayne syndrome types A (CSA; MIM #216400) and B

(CSB; MIM #133540) are autosomal recessive disorders

caused by mutation in the ERCC8 and ERCC6 genes,

respectively (Henning et al. 1995; Laugel et al. 2010).

Approximately 62 % patients diagnosed with Cockayne

syndrome carry mutations of the ERCC6 gene (Laugel

et al. 2010). The syndromes are characterized by severe

postnatal growth failure, progressive neurological dys-

function and traits reminiscent of normal aging, such as

visual impairment and sensorineural hearing loss and loss

of adipose tissue (Licht et al. 2003). ERCC (excision

repair cross-complementing) genes are part of the nucle-

otide excision repair (NER) pathway, which are respon-

sible for removing DNA lesions such as UV-induced

DNA damage. ERCC6 is a nuclear protein containing a

SWI/SNF-like ATPase domain, a nucleotide-binding

domain and an ubiquitin-binding domain (Anindya et al.

2010). Apart from NER functions, ERCC6 is also

involved in transcription regulation, chromatin mainte-

nance and remodeling (Newman et al. 2006). At the

transcriptional level, CSB cooperates with the NurD/

CHD4 complex for controlling transcription of rRNA

genes (Xie et al. 2012). In this regard, CHD4/NuRD is

involved in maintaining silenced rRNA genes but in

permissive contexts (‘‘poised’’ for transcription), whereas

CSB mediates the transition from the permissive to the

active state (Xie et al. 2012). CSB-mediated activation

could be due, at least in part, in conjunction with the

CSB–G9a interaction, to an increase in trimethylated

K9H3 and recruitment of Pol-I to chromatin (Yuan et al.

2007). A new chromatin connection for CSB has recently

been proposed (Batenburg et al. 2012). Primary fibro-

blasts derived from a CSB patient had a dysfunctional

telomere structure (Batenburg et al. 2012). CSB knock-

down was accomplished with alterations in TERRA, a

large non-coding telomere repeat-containing RNA,

resulting in alterations of telomere length and integrity

(Batenburg et al. 2012). Finally, a role for CSB in con-

trolling key mitochondrial functions in addition to the

nucleolus function has been proposed (Berquist et al.

2012).

Hum Genet (2013) 132:359–383 371

123

SRCAP mutations and Floating-Harbor syndrome

Floating-Harbor syndrome (FHS; MIM #136140) is a rare

condition characterized by proportionate short stature,

delayed osseous maturation, language deficits and a typical

facial appearance. Mutations in the SNF2-related CBP

activator protein (SRCAP) cause the FHS syndrome (Hood

et al. 2012). SRCAP expression has also been linked to

cancer, whereby it positively modulates PSA antigen

expression and promotes proliferation in prostate cancer

cells (Slupianek et al. 2010) and potentiates Notch-

dependent gene activation (Eissenberg et al. 2005). With

regard to its molecular activity, SCARP catalyzes in vitro

incorporation of the histone variant H2A.Z into chromatin

(Ruhl et al. 2006), a histone with a well-known function in

transcription regulation and cell-cycle progression. As an

example, SRCAP expression in yeast is important for the

deposition of such histone variants in specific promoters

like SP-1, G3BP and FAD synthetase (Wong et al. 2007).

Interestingly, the demethylation effect after 5-Aza-20-deoxycytidine treatment, a drug approved by the US Food

and Drug Administration (FDA) for the treatment of

hematological malignancies, requires the activity of

SCARP to introduce H2A.Z, which facilitates the acqui-

sition of nucleosome-free regions (Yang et al. 2012). On

the other hand, SRCAP is also an interaction partner of the

histone acetyltransferase CBP, meaning that SRCAP-CBP

colocalization may occur at transcriptionally active sites

(Monroy et al. 2001).

CHD7 mutations and CHARGE syndrome

The acronym CHARGE (MIM # 214800) stands for colo-

boma of the eye, heart anomaly, choanal atresia, retarda-

tion of mental and somatic development, genital and/or

urinary abnormalities and ear abnormalities and/or deaf-

ness (Sanlaville et al. 2006). It is an autosomal dominant

condition with genotypic heterogeneity, although most

cases are due to the mutation or deletion of the chromod-

omain helicase DNA-binding domain protein-7 (CHD7), a

member of SNF2-like ATP-dependent chromatin-remod-

eling enzymes (Sanlaville et al. 2006). CHD7 mutations

have been also identified in Kallmann syndrome, a devel-

opmental disorder that shares with CHARGE some phe-

notypic features such as impaired olfaction and

hypogonadism (Kim et al. 2008). Mice with heterozygous

mutations in CHD7 are a good model for studying

CHARGE syndrome, and analyses of mouse mutant phe-

notypes have demonstrated a role in the development and

function of the neuronal system. CHD7 is necessary for

mammalian olfactory tissue development and function

(Layman et al. 2009), proliferation of inner ear neuroblasts

and inner ear morphogenesis in mice (Hurd et al. 2010),

promotion of the formation of multipotent migratory neural

crest that gives rise to craniofacial bones and cartilages,

and the peripheral nervous system, amongst others (Bajpai

et al. 2010). Recent in vitro studies have suggested that

CHD7 may directly regulate BMP4 expression, a protein

involved in cartilage and bone formation, by binding with

an enhancer element downstream of the BMP4 locus (Jiang

et al. 2012). More CHD7 targets have been identified, such

as the CHD7-dependent regulation (in association with

BRG1) of SOX9 and TEIST1 genes in human neural crest

cells (Bajpai et al. 2010). Mechanisms in which CHD7

regulates downstream genes vary in a tissue- and cell-

specific manner and depend on specific binding to meth-

ylated histone H3 lysine 4 in enhancer regions (Schnetz

et al. 2009). Although further research is needed, all these

findings suggest that mutations in CHD7 could transcrip-

tionally deregulate tissue-specific genes and developmental

genes resulting in the CHARGE phenotype.

Mutations in SWI/SNF complex family genes

in Coffin-Siris syndrome and mental retardation

Coffin-Siris syndrome (CSS, MIM #135900) or ‘‘fifth

digit’’ syndrome is a multiple congenital anomaly-mental

retardation syndrome characterized by severe develop-

mental delay, coarse facial features, hirsutism and absent

fifth fingernails, toenails and distal phalanges (Santen et al.

2012). In a recent study, 87 % of patients with CSS carried

a mutation in one or more members of the SWI/SNF family

of genes, which includes SMARCB1, SMARCA4, SMAR-

CA2, SMARCE1, ARID1A and ARID1B (Santen et al. 2012;

Tsurusaki et al. 2012). Interestingly, CSS patients carrying

different genetic mutations of the SWI/SNF chromatin-

remodeling factors gave rise to similar CSS phenotypes

(Tsurusaki et al. 2012), suggesting a general role for these

complexes in coordinating chromatin conformation and

gene expression. Deregulation of the SWI/SNF complexes

is also a common feature of tumorigenesis through its

function in mammalian differentiation, proliferation and

DNA repair (Reisman et al. 2009). However, the link

between SWI/SNF mutations and intellectual disorders is

still unclear. SMARCA2 and SMARCA4 are catalytic

subunits with ATPase activity, while ARID1A and

ARID1B are structural subunits involved in target recog-

nition and protein–protein interactions (Hargreaves and

Crabtree 2011). Both types of subunit are necessary to

regulate the transcription of several genes, such as c-FOS,

vimentin, CD44, cyclins, E-cadherin and important tran-

scription factors that have been functionally linked to SWI/

SNF (Reisman et al. 2009; Santen et al. 2012).

Mutations in SMARCA2 have also been described in

patients with the Nicolaides–Baraitser syndrome (NBS,

MIM # 601358), which is characterized by severe

372 Hum Genet (2013) 132:359–383

123

intellectual disability, early-onset seizures, short stature,

dysmorphic facial features and sparse hair (Van Houdt

et al. 2012; Wolff et al. 2012). Interestingly, Harikrishnan

et al. (2005) found that SMARCA2 associates with MECP2

and regulates FMR1 gene repression in mouse fibroblasts

and human T-lymphoblastic leukemia cells. Methylation at

promoter sites specified the recruitment of MECP2/

SMARCA2; while inhibition of methylation was associated

with complex release (Harikrishnan et al. 2005). These

results highlight an interesting link between epigenetic

marks and ATPase-dependent chromatin remodeling. How

SWI/SNF deregulation produces altered expression pat-

terns of genes associated with the CSS or NBS phenotype

is not clear, although some clues about the role of the

complex in neural differentiations could help interpret

some features (Seo et al. 2005; Lessard et al. 2007).

Mutations in non-coding RNA machinery

Non-coding RNAs, defined as functional RNA molecules

that are not translated into a protein, may also contribute to

the genesis of many human disorders (Table 1) (Esteller

2011). The best characterized ncRNAs in human condi-

tions are microRNAs (miRNAs) (Croce 2009), although

other ncRNAs members are emerging, such as small

nucleolar RNAs (snoRNAs), PIWI-interacting RNAs

(piRNAs), large intergenic non-coding RNAs (lincRNAs),

long non-coding RNAs (lncRNAs) and transcribed ultra-

conserved regions (T-UCRs), among others. If we focus on

miRNAs biogenesis, miRNAs are transcribed as individual

units (named primary miRNA (pri-miRNA)). After pro-

cessing by the Drosha complex, precursor miRNAs (pre-

miRNAs) are exported from the nucleus by the protein

exportin 5 (XPO5). Further processing by Dicer and TAR

RNA-binding protein 2 (TARBP2) generates mature

miRNAs, which are included into the RNA-induced

silencing complex (RISC). Once in this complex, miRNAs

could exert their function through degradation of protein-

coding transcripts or by translational repression. ncRNAs

profiles are frequently disrupted in different types of cancer

and in non-tumoral disorders, such as imprinting disorders,

rheumatoid arthritis, Rett syndrome and Alzheimer’s dis-

ease (Esteller 2011). Widespread alterations of ncRNAs

profiles could be also a consequence of genetic mutations

of the ncRNA-associated machinery. Some recent exam-

ples in this area are discussed in this section.

TARDBP mutations and amyotrophic lateral sclerosis

10 with or without frontotemporal lobar degeneration

Amyotrophic lateral sclerosis 10 (ALS10, MIM #612069)

with or without frontotemporal lobar degeneration (FTLD)

is an autosomal dominant neurodegenerative disorder

characterized by death of the motor neurons in the brain,

brainstem and spinal cord, resulting in fatal paralysis and

respiratory failure with a typical disease course of

1–5 years. Heterozygous mutations in the TAR DNA-

binding protein 43 (TARDBP) on chromosome 1p36,

encoding for the TDP43 protein, are present in a 50 % of

individuals affected by ALS10 (Ling et al. 2010). TARD-

BP is a member of the miRNA machinery. It has a double

effect on miRNA pathway. First, it enhances precursor

miRNA (pre-miRNA) production by both interacting with

the nuclear complex of Drosha or by direct binding to the

primary miRNAs (pri-miRNAs) in the nucleus; and sec-

ondly, it binds to the terminal loops of pre-miRNAs in the

cytoplasm by interaction with the Dicer complex (Kawa-

hara and Mieda-Sato 2012). Under non-pathological con-

ditions, TARDBP is mainly localized inside the nucleus,

but altered cellular distributions, including neuronal cyto-

plasmic, intranuclear inclusions and dystrophic neurites or

glial cytoplasmic locations are found in ALS10 and FTLD

(Arai et al. 2006; Neumann et al. 2006; Lagier-Tourenne

et al. 2010). Mutant TARDBP mice models developed a

similar phenotype than human TARDBP mutation

(Wegorzewska et al. 2009). Interestingly, no cytoplasmic

aggregates were found in mice mutants; suggesting that

other mechanisms rather than toxic cytoplasmic aggrega-

tion are underlying the molecular basis of ALS degenera-

tion (Wegorzewska et al. 2009). Results are in accordance

with a recent paper in which TDP-43 depletion in differ-

entiated Neruo2a results in decreased expression of miR-

132-3p and miR-132-5p. Further research of the specific

involvement of the aforementioned miRNAS (and others to

be explored) will strongly contribute to the understanding

of the pathogenesis of ALS10.

DGCR8 mutations and DiGeorge syndrome

DiGeorge syndrome (MIM #188400) is a complex disorder

characterized by learning disabilities, characteristic facial

appearance, submucous cleft palate, conotruncal heart

defects, thymic hypoplasia or aplasia, neonatal hypocal-

cemia, psychiatric illness and susceptibility to infection

due to a deficit of T cells (Goodship et al. 1998; Shiohama

et al. 2003). DiGeorge syndrome is caused by a 1.5 to 3.0-

Mb hemizygous deletion of chromosome 22q11.2 com-

prising the DiGeorge syndrome critical region gene 8

(DGCR8) (Shiohama et al. 2003) that encodes a double

stranded RNA-binding protein that is essential for miRNA

biogenesis. Specifically, DGCR8 is required in miRNA

maturation for processing pri-miRNAs to release pre-

miRNAs in the nucleus (Han et al. 2006). Genetic modified

mouse models carrying a hemizygous chromosomal defi-

ciency on chromosome 16 that spans a segment syntenic to

Hum Genet (2013) 132:359–383 373

123

the 1.5-Mb 22q11.2 microdeletion showed alterations in

the biogenesis of a set of miRNAs in the brain (Stark et al.

2008). Furthermore, DGCR8 deficiency resulted in altera-

tions of dendritic morphology, impaired sensorimotor gatin

and memory alterations similar to human DiGeorge phe-

notype (Stark et al. 2008). Additionally, it has been also

described that inactivation of a Dgcr8 conditional allele in

neural crest cells results in cardiovascular defects (Chapnik

et al. 2012). Similar results have been found in DGCR8

conditional knock-out mice embryos and knockout vascu-

lar smooth muscle cells (Chen et al. 2012a, b). DGCR8

deficiency was associated with down-regulation of the

miR-17/92 and miR-143/145 clusters in vascular smooth

muscle cells, reduced cell proliferation and increased

apoptosis (Chen et al. 2012a, b). These data provide spe-

cific explanations for cardiovascular and neuronal defects

that could explain, at least in part, the DiGeorge syndrome

phenotype.

DICER mutations in multinodular 1 Goiter disease

Autosomal dominant multinodular Goiter (MNG, MIM

#138800) is a disorder characterized by nodular over-

growth of the thyroid gland. In MNG type 1, some females

may also develop Sertoli–Leydig ovary tumors (Rio Frio

et al. 2011). Heterozygous mutations in DICER, a gene

encoding an RNase III endonuclease essential for micr-

oRNA processing, have recently been linked to MNG

pathogenesis (Rio Frio et al. 2011). Mutations in DICER

are also associated with pleuropulmonary blastoma (Hill

et al. 2009) and play a critical role in normal cardiac

function (Chen et al. 2008). DICER contains two RNase III

domains and a PAZ domain, a module that binds the end of

double-strand RNA (Macrae et al. 2006). Familial MNG

shows clear selective disruption of the PAZ domain, sug-

gesting a potential role of this domain in thyroid devel-

opment (Rio Frio et al. 2011). At the functional level,

lymphoblasts taken from MNG patients showed altered

miRNA compared with control profiles (i.e., LET7A and

miR345), suggesting a dysregulation of gene expression

patterns (Rio Frio et al. 2011). Further determination of the

consequences of specific microRNAs synthesis could be an

important topic for future research into MNG and other

DICER-associated pathologies.

Therapeutic applications of epigenetics

One of the main characteristics of epigenetic mechanisms

is their reversibility, making them potentially powerful

tools for curative pharmacological therapy (Fig. 1). Reac-

tivation of epigenetically silenced genes has been possible

for years by the treatment with DNA demethylation drugs,

such as zebularine or 5-aza-20-deoxycytidine (5-ADC), or

with histone deacetylase (HDAC) inhibitors, including

SAHA (suberoylanilide hydroxamic acid), valproic acid

(VPA) and trichostatin A (TSA). Indeed, some of these

drugs have significant antitumoral activity and the FDA has

approved the use of several of them for treating patients

(Kaminskas et al. 2005; Fiskus et al. 2008; Scuto et al.

2008). This approval has sparked a dramatic increase in the

development and trials of ‘‘epigenetic drugs’’ for treating

cancer and neural diseases (Kazantsev and Thompson

2008; Heyn and Esteller 2012). Although the most

advanced clinical trials are those corresponding to cancer

treatment, interest has grown in the fields of neurological

and neurodegenerative diseases in recent years (Day and

Sweatt 2012). The possibilities have only just begun to be

explored in human patients, but the basis of this therapy

has been confirmed in animal models.

Rubinstein–Taybi syndrome (RSTS) is probably the best

model for studying the therapeutic uses of HDAC inhibi-

tors that could compensate for the deficiency of HAT

activity (CBP mutations). RSTS has been modeled in mice,

and several heterozygous cbp ± mice (homozygous

cbp -/- mutants are embryonic lethal) have been gener-

ated (Alarcon et al. 2004). These models feature deficits in

long-term memory and cognitive impairments reminiscent

of human RTS neural symptoms, confirming the role of

CBP in the etiology of the disease. At the molecular level,

these mice have reduced HAT activity, decreased acetyla-

tion of specific histone proteins and impaired CBP-depen-

dent gene expression (Alarcon et al. 2004). Treatment with

HDAC inhibitors, such as SAHA or TSA, ameliorate defi-

cits in synaptic plasticity and cognition in cbp ± mice

(Hallam and Bourtchouladze 2006; Vecsey et al. 2007) by

enhancing transcriptional expression of specific neuronal

genes. In a similar manner, immortalized human lympho-

cytes derived from patients with RSTS showed reduced

acetylation levels, which primarily affect histones H2A and

H2B, compared to the histone acetylation levels of

immortalized human lymphocytes derived from patients

with Cornelia de Lange syndrome (a neurological disorder)

or healthy controls (Lopez-Atalaya et al. 2012). Interest-

ingly, the acetylation deficits in RSTS cells were rescued by

treatment with TSA (Lopez-Atalaya et al. 2012).

Some therapeutic approaches have been investigated in

Rett syndrome. Mecp2 knock-out mice also exhibit the

neurodevelopmental phenotype characteristic of human

Rett syndrome (Shahbazian et al. 2002). The cognitive

defect of MeCp2-deficient mice can be reverted by MecP2-

induced overexpression in mice (Collins et al. 2004) and in

MeCp2-deficient astrocytes (Lioy et al. 2011), suggesting

that this might well be an effective treatment for Rett

syndrome. Apart from this gene therapy strategy, which is

not really applicable in humans, pharmacological treat-

ments based on epigenetic targets are beginning to be

374 Hum Genet (2013) 132:359–383

123

explored as more feasible therapeutic interventions. Since

MeCP2 binds directly to methylated promoters in associ-

ation with the corepressor complex Sin3 and HDAC,

another therapeutic strategy could be based on targeting

HDAC activity. It has been widely demonstrated that

HDAC inhibitors enhance memory formation and neuronal

postnatal formation in various experimental models

(Kazantsev and Thompson 2008). There are some exam-

ples of the benefits of such treatments in the literature: the

alleviation of motor deficits in mouse models of Hunting-

ton disease by injections of SAHA (Hockly et al. 2003); the

delay of neurodegeneration and tauopathy in a mouse

model of Alzheimer’s disease through the activation of

SIRT1 by means of resveratrol treatments (Kilgore et al.

2010); and the reactivation of the frataxin genes by treat-

ments with benzamide-based HDAC inhibitors in immor-

talized cultured cells from Friedrich’s Ataxia syndrome

patients (Herman et al. 2006).

However, many questions remain unsolved concerning

drug potency, selectivity and permeability. Treatment with

HDAC inhibitors results in the re-expression of a limited

number of memory-associated genes (Vecsey et al. 2007).

This raises a question: are HDAC inhibitors’ treatments

potentially able to restore all types of genes? Or by contrast

do more ‘‘easier reverted’’ genes exist that can be phar-

macologically manipulated? If reversion is conditioned to

any factor (i.e., their genomic context or the acetylation

level) HDAC treatments would be more effective in certain

diseases than others. Multiple epigenetic enzymes could

contribute to a specific mark (especially histone acetyla-

tion) and furthermore, manipulating histone modifications

could also affect DNA methylation. Which is the best

target for inducing specific gene re-expression? Should

systemic or enzyme-targeted drugs be employed? This lack

of specificity means that almost none of the available

epigenetic drugs are isoform-specific and, for instance,

HDAC inhibitors have binding affinities for different

HDACs isoforms (Kilgore et al. 2010). It is expected that

development of subclass-specific inhibitors might contrib-

ute to minimize the side effects of the epigenetic therapy.

On the other hand, the tissue also influences its effective-

ness. DNA demethylating drugs are deoxycytidine analogs

that must be incorporated into the DNA after replication

cycles. As a consequence, the ‘‘speed’’ of base substitution

is strongly influenced by the rate of cell division. It is to be

expected that such DNA demethylating treatments will not

be very effective in neuronal cells with few or no cell

divisions. Further knowledge about the pathogenesis and

identification of the molecular/regulatory pathways that are

altered in the disease will enable the optimal target to be

identified and the therapeutic potential of epigenetic-based

drugs to be exploited. Despite these difficulties, epigenetic-

based therapy may become a successful intervention in the

treatment of human disorders associated with epigenetic

alterations.

Acknowledgments This work was supported by grants from the

European Research Council (Advanced EPINORC), the Fondo de

Investigaciones Sanitarias (PI08-1345 and PI10/02267), the Ministe-

rio de Ciencia e Innovacion (SAF2011-22803), the Fundacio La

Marato de TV3 (111430/31), European COST Action TD09/05, and

the Health Department of the Catalan Government (Generalitat de

Catalunya). M.E. is an Institucio Catalana de Recerca i Estudis

Avancats Research Professor.

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