Lesson 2 Monogenic disorders Mendelian inheritance

Lesson 2Monogenic disorders Mendelian inheritance

Mendelian pedigree patterns

mendelian genetic character

• depends on the genotype at one single locus• expression of any human character typically depends on several/many genes and environmental factors

• >10.000 mendelian characters are known• OMIM internet database (http://www.ncbi.nlm.nih.gov/Omim/)

• dominant vs recessive• semi-dominant• hemizygosity

Mendelian pedigree patterns

Mendelian pedigree patterns

Mendelian pedigree patterns

autosomal dominant inheritance

• one affected parent• affects either sex• transmitted by either sex• 50% recurrence risk• ex: achondroplasie, Huntington’s chorea, Steinert muscular dystrophy, neurofibromatosis, Marfan syndrome, polycystic kidneys

Mendelian pedigree patterns

Mendelian pedigree patterns

autosomal recessive inheritance

• unaffected parents• parents are unaffected carriers• parental consanguinity• affects either sex• 25% recurrence risk, 25% carrier• ex: cystic fibrosis, metabolic disorders

Mendelian pedigree patterns

Mendelian pedigree patterns

X-linked recessive inheritance

• affects mainly males• unaffected parents• mother asymptomatic carrier• affected males in maternal lineage• no male to male transmission (why?)• sons of carrier mother have a 50% recurrence risk• daughters of carrier mother have a 50% chance to be carrier

Mendelian pedigree patterns

Mendelian pedigree patterns

X-linked dominant inheritance

• affects either sex, more females• affected parent• females often more mildly affected• 50% recurrence risk for child of affected mother• 100% and 0% RR for daughters and sons resp of affected male

Mendelian pedigree patternstype of inheritance???

• infer from pedigree analysis • limitations

families vs experimental animalssingle pedigrees – few affectedfamily ascertainment bias

‘informed guess’ for rare conditionsconsequences for genetic counseling

unravel molecular pathology

Mendelian pedigree patternsfurther complications

non penetrance (NP)

Mendelian pedigree patternsfurther complications

variable expression

Mendelian pedigree patternsfurther complications

imprinting

Mendelian pedigree patternsfurther complications

I

II

III

III- 1 new mutation

II-1 new mutation

II-1 germline mosaicism

I-2 germline mosaicism

germinal mosaicism

Mendelian pedigree patternsfurther complications anticipation = phenotypic severity increases

with each generation

I

II

III

Age of onset grandmother < fatherAffected fetus diagnosed prenatally

Mendelian pedigree patternsmolecular pathology

main classes of mutation

• deletions 1bp up to Mbs• insertions including duplications• single base substitutions

missense: AA changenonsense: stop codonsplice site mutation

• frameshifts• dynamic mutations

Mendelian pedigree patternsmolecular pathology

mutation nomenclature

Amino acid substitutionsone or three-letter codes for AAnumber/position of the AAeg: R117H or Arg117His

Nucleotide substitutionATG initiator codon is +11162G>A

Mendelian pedigree patternsmolecular pathology

Loss of function mutations

• recessive phenotypes:50% of the normal level is sufficient

• haploinsufficiency:50% reduction leads to phenotypedominant

• dominant negative: nonfunctional productinterferes with function of normal proteineg: fibrillar collagen, proteins that dimerize

Mendelian pedigree patternsmolecular pathology

Loss of function mutations(typically more heterogeneous)

• deletions, insertions, • unstable expanding repeats• gene disruption by translocation or inversion• promotor inactivation by mutation or methylation

Mendelian pedigree patternsmolecular pathology

Loss of function mutations(typically more heterogeneous)

• mRNA destabilisation by polyadenylation site mutation • mRNA destabilisation by nonsense-mediated RNA decay• epigenetic modification

DNA methylation/imprintingchanges in chromatin configuration

Mendelian pedigree patternsmolecular pathology

Loss of function mutations

• mutations influencing splicing i.e. inactivating donor splice site, inactivating acceptor splice site, activating a cryptic splice site• frameshift, nonsense, missense• prevent posttranscriptional processing• prevent correct cellular localisation of product

Mendelian pedigree patternsmolecular pathology Loss of function mutations

cystic fibrosis

• most frequent autosomal recessive disorder• prevalence: 1/2500 newborns• carrier frequence 1/25

Mendelian pedigree patternsmolecular pathology Loss of function mutations

CF• clinical symptoms:

viscid mucus in lungspancreatic insufficiencymeconium ileusmale infertility

• chronic disorder• life expectance 1955: < 5 yr

present: 30-35 yr

Mendelian pedigree patternsmolecular pathology Loss of function mutations

• imbalance in water and ion transport in secreting epithelia• excessive salt loss in sweat• ‘84 normal efflux of chloride ions across epithelial cell membranes in response to cAMP increase is deficient

CF, putative protein function

Mendelian pedigree patternsmolecular pathology Loss of function mutations

• locus assignement to 7q31 using linkage analysis • cloning through physical mapping• genomic sequence 250 kb coding sequence 6.5 kb• almost exclusively expressed in epithelial cells• 3bp deletion in exon 10 in 70% in CF patients• CFTR = cystic fibrosis conductance regulator

CF, gene identification

ion channel belonging to gene family involved in active transport across the cell membrane ABC (ATP binding casette) gene family

CF, gene function

protein structure2 hydrophobic transmembrane domains1-2 nucleotide binding folds (bind and cleace ATP)R-domain: target for PKA mediated serine phophorylation

phosphorylation of R-domainbinding of ATPopening of the chloride channel

CF, gene function

CF, mutation spectrum

Mendelian pedigree patternsmolecular pathology

Unstable expanding repeats

• first discovered in 1991• triplet repeats

very large expansions of repeatsoutside coding sequences

FRAXA Xq27.3 5’UT CGG stable 6-54 unstable 200-1000

Mendelian pedigree patternsmolecular pathology

Unstable expanding repeats

Mendelian pedigree patternsmolecular pathology

Unstable expanding repeats

triplet repeats modest expansions of CAG repeatswithin coding sequences

HD 4p16.3 coding (CAG)n stable 6-35 unstable 36- >100

polyglutamine tracts lead to aggregations and cell death

Mendelian pedigree patternsmolecular pathology

Mendelian pedigree patternsmolecular pathology

gain of function mutations

• less common• possible effects are

overexpressionreceptor ‘on’new substrateion channel open

Mendelian pedigree patternsmolecular pathology

one gene

genetic variability: severity of phenotype depends upon type of mutation

different mutations cause different(related) syndromes

Mendelian pedigree patternsmolecular pathology

different mutations cause different (related) syndromes

Mendelian pedigree patternsmolecular pathology

one gene

loss of function vs gain of function

RET gene = receptorlof - Hirschsprung’s diseasegof - fam. medullary thyroid ca

MEN2

Mendelian pedigree patternsmolecular pathology

one gene

intrafamilial variability due to modifier genes

tyrosinase deficiency causesocular albinism

R402Q common variantin association with MITF mutationcauses OA

Mendelian pedigree patternsmolecular pathology

one phenotype, several genes

profound deafnesscompound heterozygosity