lesson 2 monogenic disorders mendelian inheritance
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Lesson 2 Monogenic 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 - PowerPoint PPT PresentationTRANSCRIPT
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Lesson 2Monogenic disorders Mendelian inheritance
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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
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Mendelian pedigree patterns
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Mendelian pedigree patterns
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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
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Mendelian pedigree patterns
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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
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Mendelian pedigree patterns
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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
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Mendelian pedigree patterns
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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
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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
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Mendelian pedigree patternsfurther complications
non penetrance (NP)
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Mendelian pedigree patternsfurther complications
variable expression
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Mendelian pedigree patternsfurther complications
imprinting
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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
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Mendelian pedigree patternsfurther complications anticipation = phenotypic severity increases
with each generation
I
II
III
Age of onset grandmother < fatherAffected fetus diagnosed prenatally
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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
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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
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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
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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
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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
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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
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Mendelian pedigree patternsmolecular pathology Loss of function mutations
cystic fibrosis
• most frequent autosomal recessive disorder• prevalence: 1/2500 newborns• carrier frequence 1/25
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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
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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
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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
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ion channel belonging to gene family involved in active transport across the cell membrane ABC (ATP binding casette) gene family
CF, gene function
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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
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CF, mutation spectrum
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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
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Mendelian pedigree patternsmolecular pathology
Unstable expanding repeats
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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
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Mendelian pedigree patternsmolecular pathology
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Mendelian pedigree patternsmolecular pathology
gain of function mutations
• less common• possible effects are
overexpressionreceptor ‘on’new substrateion channel open
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Mendelian pedigree patternsmolecular pathology
one gene
genetic variability: severity of phenotype depends upon type of mutation
different mutations cause different(related) syndromes
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Mendelian pedigree patternsmolecular pathology
different mutations cause different (related) syndromes
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Mendelian pedigree patternsmolecular pathology
one gene
loss of function vs gain of function
RET gene = receptorlof - Hirschsprung’s diseasegof - fam. medullary thyroid ca
MEN2
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Mendelian pedigree patternsmolecular pathology
one gene
intrafamilial variability due to modifier genes
tyrosinase deficiency causesocular albinism
R402Q common variantin association with MITF mutationcauses OA
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Mendelian pedigree patternsmolecular pathology
one phenotype, several genes
profound deafnesscompound heterozygosity