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Lesson 2 Monogenic disorders Mendelian inheritance PowerPoint PPT Presentation


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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

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Lesson 2 Monogenic disorders Mendelian inheritance

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Lesson 2 monogenic disorders mendelian inheritance

Lesson 2

Monogenic disorders

Mendelian inheritance


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

  • >10.000 mendelian characters are known

  • OMIM internet database (http://www.ncbi.nlm.nih.gov/Omim/)

  • dominant vs recessive

  • semi-dominant

  • hemizygosity


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns


Lesson 2 monogenic disorders mendelian inheritance

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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns


Lesson 2 monogenic disorders mendelian inheritance

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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns


Lesson 2 monogenic disorders mendelian inheritance

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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns


Lesson 2 monogenic disorders mendelian inheritance

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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

type of inheritance???

  • infer from pedigree analysis

  • limitations

  • families vs experimental animals

  • single pedigrees – few affected

  • family ascertainment bias

  • ‘informed guess’ for rare conditions

  • consequences for genetic counseling

  • unravel molecular pathology


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

further complications

non penetrance (NP)


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

further complications

variable expression


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

further complications

imprinting


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

further complications

germinal mosaicism

I

II

III

III- 1 new mutation

II-1 new mutation

II-1 germline mosaicism

I-2 germline mosaicism


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

further complications

anticipation = phenotypic severity increases

with each generation

I

II

III

Age of onset grandmother < father

Affected fetus diagnosed prenatally


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

  • main classes of mutation

  • deletions 1bp up to Mbs

  • insertions including duplications

  • single base substitutions

  • missense: AA change

  • nonsense: stop codon

  • splice site mutation

  • frameshifts

  • dynamic mutations


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

mutation nomenclature

Amino acid substitutions

one or three-letter codes for AA

number/position of the AA

eg: R117H or Arg117His

Nucleotide substitution

ATG initiator codon is +1

1162G>A


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Loss of function mutations

  • recessive phenotypes:

  • 50% of the normal level is sufficient

  • haploinsufficiency:

  • 50% reduction leads to phenotype

  • dominant

  • dominant negative: nonfunctional product

  • interferes with function of normal protein

  • eg: fibrillar collagen, proteins that dimerize


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular 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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular 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/imprinting

  • changes in chromatin configuration


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular 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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Loss of function mutations

  • cystic fibrosis

  • most frequent autosomal recessive disorder

  • prevalence: 1/2500 newborns

  • carrier frequence 1/25


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Loss of function mutations

  • CF

  • clinical symptoms:

  • viscid mucus in lungs

  • pancreatic insufficiency

  • meconium ileus

  • male infertility

  • chronic disorder

  • life expectance 1955: < 5 yr

  • present: 30-35 yr


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Loss of function mutations

CF, putative protein function

  • 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


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Loss of function mutations

CF, gene identification

  • 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


Lesson 2 monogenic disorders mendelian inheritance

CF, gene function

ion channel belonging to gene family involved

in active transport across the cell membrane

ABC (ATP binding casette) gene family


Lesson 2 monogenic disorders mendelian inheritance

CF, gene function

protein structure

2 hydrophobic transmembrane domains

1-2 nucleotide binding folds (bind and cleace ATP)

R-domain: target for PKA mediated serine phophorylation

phosphorylation of R-domain

binding of ATP

opening of the chloride channel


Lesson 2 monogenic disorders mendelian inheritance

CF, mutation spectrum


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Unstable expanding repeats

  • first discovered in 1991

  • triplet repeats

  • very large expansions of repeats

  • outside coding sequences

  • FRAXA Xq27.3 5’UT

  • CGG stable 6-54 unstable 200-1000


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Unstable expanding repeats


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

Unstable expanding repeats

triplet repeats

modest expansions of CAG repeats

within coding sequences

HD 4p16.3 coding

(CAG)n stable 6-35 unstable 36- >100

polyglutamine tracts lead to aggregations and cell death


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

gain of function mutations

  • less common

  • possible effects are

  • overexpression

  • receptor ‘on’

  • new substrate

  • ion channel open


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

one gene

genetic variability:

severity of phenotype depends upon type of mutation

different mutations cause different

(related) syndromes


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

different mutations cause different (related) syndromes


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

one gene

loss of function vs gain of function

RET gene = receptor

lof - Hirschsprung’s disease

gof - fam. medullary thyroid ca

MEN2


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

one gene

intrafamilial variability due to

modifier genes

tyrosinase deficiency causes

ocular albinism

R402Q common variant

in association with MITF mutation

causes OA


Lesson 2 monogenic disorders mendelian inheritance

Mendelian pedigree patterns

molecular pathology

one phenotype, several genes

profound deafness

compound heterozygosity


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