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nature genetics • volume 23 • october 1999 127

A number of genetic disorders seem toattract more than their fair share of atten-tion from human and medical geneticists.Some diseases (such as cystic fibrosis)achieve this status because they are quitecommon and exact a substantial toll onboth patients and the medical commu-nity. Others (such as fragile-X syndrome)do so because they present with unusualgenetic or clinical features that defy con-ventional explanations. Discovery of thegenetic and molecular basis of suchdisorders, therefore, promises toreveal new concepts or mechanismsof genetic disease, the significanceand general interest of which extendfar beyond the details of the partic-ular disorder itself.

One such disorder is Rett syn-drome (RTT), a childhood neuro-developmental disorder that affectsfemales (almost exclusively). Itsgenetic basis has been difficult toestablish, because most cases aresporadic. Moreover, affected girls areconsidered to have normal develop-ment for the first 6 to 18 months,followed by a period of regression(sometimes abrupt), marked in par-ticular by loss of purposeful handuse and speech. Hand-wringing (seefigure), ataxia and growth retarda-tion often accompany a profoundmental handicap1.

X marks the spot?A number of models that accountfor the genetics of RTT have beenproposed. The simplest explanation is thatRTT is an X-linked dominant condition,lethal in hemizygous males. The absence,however, of a convincing deficit of malescontrasts with other X-linked disorders ofthis type2. A high proportion of de novomutations (particularly in the paternalgerm line) might account for the absenceof obvious male lethality, but the incidenceof RTT (an estimated 1 in 10,000) wouldrequire a very high mutation rate. Therecognition of an X-linked dominant dis-order with male sparing3 provides anothermodel. Because of the sex-limited expres-sion of RTT, most attempts to identify thecausative gene have centred on the X chro-mosome. Tantalizing, but inconsistent,hints of skewed X-chromosome inactiva-

tion in females with RTT or their mothersalso implicate the X (refs 4,5). Whereasattempts to map the gene have been hin-dered by the frustratingly small number offamilial RTT cases available, exclusionmapping based on comparison of X-chro-mosome haplotypes among affected sistersor half-sisters has focused attention onXq28 (ref. 5).

Ruthie Amir and colleagues6 nowreport (see page 185) the fruits of their

labours over Xq28: the presence of severalmutations in MECP2 in a proportion ofRTT patients. The methyl CpG-bindingprotein 2 (MeCP2) can bind methylatedDNA and has been implicated as a keyplayer in assembling transcriptionalsilencing complexes7. These data provide alink between the genetics of RTT and epi-genetic silencing and establish RTT as thefirst human disease caused by defects in aprotein involved in DNA methylation.Notably, they add RTT to the small, butgrowing, number of human genetic disor-ders that involve abnormal chromatinpackaging and gene expression.

A relationship between chromatinstructure, gene expression and DNAmethylation has long been recognized7,

but the role of methylation in vertebratedevelopment is poorly defined. Indeed,the only genes whose appropriate expres-sion patterns are known to depend onmethylation are those whose CpG islandsneed to become methylated for epige-netic silencing8.

Silence the noiseThe MeCP2 protein silences methylatedchromatin by recruiting a histone deacety-

lase complex7. Unlike most otherknown transcriptional repressorproteins, however, the binding siteof MeCP2 occurs frequently in ver-tebrate genomic DNA, as it requiresonly a single methylated CpG basepair to bind9. What might be therole of such a ubiquitous transcrip-tional repressor? It has been pro-posed that MeCP2 acts as a globaltranscriptional repressor that pre-vents unscheduled transcriptionthroughout the genome10. Couldthe pathology of RTT patients becaused by excessive transcriptional‘noise’ owing to a silencing defect?The fact that RTT patients do notsuffer severe abnormalities duringearly development implies that nospecific programmes of develop-mental gene expression (includingX-chromosome inactivation) aredisrupted in the absence of MeCP2.But if genomic noise is to blame,why is the brain the primary site ofpathology? MeCP2 is more abun-dant in the brain than in any other

tissue, so perhaps the brain is more sensi-tive to excess transcriptional noise thanare other tissues10. Alternatively, perhapsmore MeCP2 is needed to keep noise toan acceptable level in the brain than inother tissues. But although a defect ingene silencing is a logical and excitingpossibility in RTT, it remains unproven.Genes that are targets of MeCP2 (whetherspecific or more global) need to be identi-fied and their possible over- or mis-expression in RTT, particularly in thenervous system, evaluated.

The finding that MECP2 is mutated inRTT fits well with what is known aboutMeCP2 deficiency in mice11. Male mouseembryonic stem (ES) cells in which Mecp2is disrupted cannot support development,

Breaking the silence in Rett syndromeHuntington F. Willard1 & Brian D. Hendrich2

1Department of Genetics, Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.2Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, UK. e-mail: hfw@po.cwru.edu and brian.hendrich@ed.ac.uk

Rett syndrome. A typical symptom of Rett syndrome is constanthand-wringing. Other symptoms (although not observed in thisgirl) include spasticity, scoliosis and a vacant stare. Image kindly sup-plied by Huda Zoghbi.

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128 nature genetics • volume 23 • october 1999

consistent with the possible male lethalityof RTT. In contrast, chimaeric mice, inwhich a small proportion of cells arederived from MeCP2-deficient ES cells,are viable. These animals might provide amodel for RTT, as female RTT patients arealso mosaic for MeCP2-expressing andMeCP2-deficient cells because of randomX-chromosome inactivation. Conditionalmouse mutants, in which Mecp2 is specifi-cally disrupted in the brain, may providefurther clues as to the reasons for the spe-cific neurodevelopmental effects ofMeCP2 deficiency.

MeCP2 is but one of three proteinsknown to both bind specifically to methy-lated DNA in vivo and to be capable ofrepressing transcription12. Might othermethyl-binding family members also fac-tor in RTT, given that MECP2 mutationshave been found in a proportion ofpatients? As the genes for other methyl-binding proteins are autosomal, mutationof them is unlikely to cause RTT, unlessthere are autosomal phenocopies.Nonetheless, the discovery that mutations

in a gene that affects DNA methylationlead to human disease implicates the auto-somal genes as candidates for other neuro-logical disorders.

Documentation of MECP2 mutationsby Amir et al.6 identifies RTT as one of asmall but growing number of humandiseases involving abnormal chromatinassembly or remodelling, with conse-quent epigenetic effects on expression ofone or more genes that are themselvesnot mutated. Other examples includepatients with imprinting defects13,14 whodemonstrate inappropriate gene expres-sion due to alterations in epigenetic reg-ulation. Similarly, patients withabnormal X chromosomes that are miss-ing the X-inactivation centre fail to inac-tivate that X and therefore havefunctional disomy of X-linked genes2.Recently, Allis and colleagues15 discov-ered a defect in phosphorylation of his-tone H3 in Coffin-Lowry syndrome,suggesting that its pathogenesis may beeffected by global abnormalities in geneexpression. So, these examples focus

renewed attention on chromatin as acritical, but often overlooked, compo-nent in the cascade of regulatory mecha-nisms that not only underlie geneactivation or silencing, but are also rele-vant to human disease. �

1. Clarke, A. J. Med. Genet. 33, 693–699 (1990).2. Willard, H.F. in The Metabolic and Molecular Bases

of Inherited Disease, (eds Scriver, C.R.)(McGraw-Hill, New York, in press).

3. Ryan, S.G. et al. Nature Genet. 17, 92–95 (1997).4. Zoghbi, H.Y., Percy, A.K., Schultz, R.J. & Fill, C.

Brain Dev. 12, 131–135 (1990).5. Sirianni, N., Naidu S., Pereira, J., Pillotto, R.F. &

Hoffman, E.P. Am. J. Hum. Genet. 63, 1552–1558(1998).

6. Amir, R.E. et al. Nature Genet. 23, 185–188(1999).

7. Ng, H.H. & Bird, A. Curr. Opin. Genet. Dev. 9,158–163 (1999).

8. Jaenisch, R. Trends Genet. 13, 323–329 (1997).9. Lewis, J.D. et al. Cell 69, 905–914 (1992).10. Nan, X., Campoy, F. & Bird, A. Cell 88, 471–481

(1997).11. Tate, P., Skarnes, W. & Bird, A. Nature Genet. 12,

205–208 (1996).12. Hendrich, B. & Bird, A. Mol. Cell. Biol. 18,

6538–6547 (1998).13. Nicholls, R.D., Saitoh, S. & Horsthemke, B. Trends

Genet. 14, 194–200 (1998).14. Lee, M.P. et al. Proc. Natl Acad. Sci. USA 96,

5203–5208 (1999).15. Sassone-Corsi, P. et al. Science 285, 886–891

(1999).

A friendly signalPamela L. Schwartzberg

Genetic Disease Research Branch, National Human Genetic Disease Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. e-mail: pams@nhgri.nih.gov

Factors involved in the development andprogression of leukaemia have provided awealth of information about the genes andpathways regulating normal cellulargrowth, in addition to the abnormalprocesses associated with malignant trans-formation. The study of RNA tumourviruses or retroviruses has led to many ofthe seminal observations in this field.These include the characterization ofoncogenes carried or activated by theseviruses, and secondary genetic changescontributing to the oncogenic process.Derek Persons and colleagues now providea new installment in these studies, inworking out how the Fv2 locus conferssusceptibility to disease induced by theFriend erythroleukaemia virus complex1

(see page 159).Induction of erythroleukaemia by the

Friend virus complex requires two com-ponents: the replication-competentFriend virus (FV), which drives viral pas-sage; and the associated replication-defective spleen focus-forming virus(SFFV), which is responsible for ery-

throblastosis, the proliferation of ery-throid precursors characteristic of thefirst stage of Friend disease2. Theleukaemia caused by the Friend viruscomplex is distinctive in that the genomeof SFFV, unlike those of other replica-tion-defective retroviruses that inducetumours, does not contain an oncogene.Instead, pathogenicity is associated withexpression of gp55, a recombinant, trun-cated form of the viral envelope glycopro-tein2. The gp55 protein binds andstimulates erythropoietin receptorsexpressed in the same cells3 (see figure),leading to increased replication of theerythroid precursors known as BFU-Eand CFU-E. Progression to frankleukaemia is associated with subsequentgenetic changes in these proliferativecells, including loss of TP53 and overex-pression of the gene encoding the Sp.1transcription factor4,5.

Other factors also influence the devel-opment and progression of ery-throleukaemia induced by Friend virus,as is indicated by the fact that several

genetic loci confer susceptibility or con-tribute to the progression of the disease.At least two of these encode endogenous‘retroviral’ proteins that interefere withviral replication. Fv1 encodes an endoge-nous ‘viral’ Gag protein2, and Fv4, anendogenous ‘viral envelope’ protein2.Although these are important for viralreplication and are noteworthy in them-selves (for example, Fv1 may provide amodel for a dominant interfering Gagmutant—and may therefore snag theattention of those who seek to inhibitHIV replication), they do not tell usabout the initiation or progression ofleukaemia. Other loci, however, directlyinfluence progression of the disease, so arerelevant to the development of leukaemiaand to normal haematopoiesis. Fv2 is onesuch locus2. It does not affect viral repli-cation; rather, it determines whetherexpression of gp55 causes proliferation oferythroblasts. It has been suggested thatthis genetic locus influences the ability ofgp55 to interact with and stimulate theerythropoietin receptor2.

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