more than half of mendelian phenotypes are autosomal dominant examples: familial...
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More than half of Mendelian phenotypes are autosomal dominant
Examples: Familial hypercholesterolemia Myotonic dystrophy Huntington disease Neurofibromatosis Polycystic kidney disease** Achondroplasia--------------------------------------------------------** Less common AR form exisits
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In typical AD inheritance, every affected person in a pedigree has an affected parent
This is also true for X-linked dominant traits
Male-to-male transmission can readily distinguish AD phenotypes
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Familial Familial hypercholesterolemiahypercholesterolemia
?
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P
What is the probability that this pregnancy will be
affected?
A a
a
a Aa
Aa
unaffected
Maternal
Paternal
Punnett Square“a” = normal allele“A” = mutant allele
aa
aa
1/2 1/2
1/2
1/2
affected
Aa
Aa
1/4 1/4
1/4 1/4
1/2
+
1/2
+
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New alleles arise by mutation and are maintained or removed by selection
Survival of new mutation in the population depends on the fitness of persons carrying it as compared to persons with other alleles at the locus concerned
Many autosomal dominant disorders are associated with reduced fitness
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• Fitness-probability of transmitting one’s genes to the next generation
• 0 if having the disorder eliminates the ability to reproduce--ex. Death by age of reproduction
• 1 if the same ability to reproduce as gen. pop.
If the fitness is 0, all affected individuals must be due to new mutations
If the fitness is 1, i.e., the onset of the disorder is after reproduction and therefore does not affect it, a patient is more likely to have inherited the disorder
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FITNESS - the relative reproductive success of a particular phenotype, between 0 and 100%. It may be reduced by decreased survival to the age of reproduction or diminished fertility.
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Hutchinson-Gilford Progeria
• Autosomal Dominant, Zero Fitness• Always the Result of a New Mutation• Reported to occur in 1 in 4 million newborns worldwide
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Autosomal Dominant disorders frequently have differences in expression of mutant genes
1. Penetrance: probability of any phenotype all or none concept
2. Expressivity: severity of the phenotype in individuals with the same genotype
3. Pleiotropy: a genetic defect results in diverse phenotypic effects
Example: Neurofibromatosis
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Neurofibromatosis (NF1)-common disorder of the nervous system
1. Multiple benign fleshy tumors (neurofibromas) in the skin
Neurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people worldwide
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Neurofibromatosis (NF1)-common disorder of the nervous system
2. Multiple flat, irregular pigmented skin lesions known as café au lait spots
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Neurofibromatosis (NF1)-common disorder of the nervous system
3. Small benign tumors (hamartomas) on the iris of the eye
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Neurofibromatosis (NF1)-common disorder of the nervous system
4. Less frequently, mental retardation, CNS tumors, diffuse plexiform neurofibormas and the development of cancer of the NS or muscle
Adult heterozygotes almost always demonstrate some signof the disease Penetrance is 100% but age-dependent
Phenotype ranges from café au lait spots to tumors of the spinal cord Variable expressivity
Pleiotropic affects skin, iris, brain, muscle
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Pedigree of a family with NF-1, apparently originating as a new mutation in the proband
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Example: Split-hand deformity (lobster-claw malformation) a type of ectrodactyly
This female is non-penetrant
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Example: BRCA2 Familial Breast Cancer
Although men can get breast cancer, penetrance is much lower than in woman who inherit BRCA2 mutations
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Example: Huntington Disease
What is the probability that she has inherited a huntingtin mutation
?0 8030
100
25
age in years
% a
ffect
ed
given that she's unaffected at 30?
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Genotypes do not act in isolation Interaction with the wild-type allele Interaction with other loci Interaction with the environment Not known!
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Matings that could produce homozygous offspring are rare (A/a x A/a, A/A x A/a or A/A x A/A)
Disorders are usually more severe in homozygotes
Example 1: Achondroplasia: a skeletal disorder of short-
limb dwarfism and large head size Marriage b/w achondroplastic (heterozygotes)
is common Homozygous achondroplastic patients are
much more severely affected & commonly do not survive early infancy
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Short limbs, a normal-sized head and body, normal intelligence
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Fibroblast growth factor receptor 3 Inhibits bone growth by inhibiting chondrocyte
proliferation and differentiation
Mutation causes the receptor to signal even in absence of ligand
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extracellular
intracellular
Normal FGFR3 signalingNormal FGFR3 signaling
FGFR3FGFR3FGF ligandFGF ligand
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extracellular
intracellular
Normal FGFR3 signalingNormal FGFR3 signaling
Inhibition of bone growthInhibition of bone growth
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extracellular
intracellular
AchondroplasiaAchondroplasia
• Receptor signals in absence of ligandReceptor signals in absence of ligand• Bone growth attenuatedBone growth attenuated
Gly380Arg mutation in transmembrane domain
**
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Example 2: familial hypercholesterolemia, an AD
disorder leading to premature coronary heart disease
Homozygotes have a very severe disease with much shorter life expectancy as compared to heterozygotes
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Cutaneous xanthomas in a familial hypercholesterolemia homozygote.
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HD is a neurodegenerative disease characterized by progressive dementia and abnormal movements
HD is an exception in that severity of the disorder (clinical expression) is the same in heterozygotes and homozygotes (onset age?)
HD homozygotes can be distinguished from heterozygotes by molecular analysis of mutant gene
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Defect is autosomally transmitted but expressed in only one sex
Example: male-limited precocious puberty (familial
testotoxicosis), an AD disorder, affected boys develop 2º sexual characteristics and adolescent growth spurt at ~ 4 yrs
In some families, mutation is in leutinizing hormone receptor gene (mutant receptor signals without hormone).
The defect is non-penetrant in heterozygous females (another example of sex-dependent penetrance)
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Pedigree pattern of male-limited precocious puberty. This AD disorder can be transmitted by affected males or by unaffected carrier females. Male-to-male transmission shows that inheritance is not X-linked. Because the trait is transmitted through unaffected carrier females, it can not be Y-linked.
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• phenotype appears in phenotype appears in everyevery generation generation
• each each affected personaffected person has an has an affected parentaffected parent (exceptions!) (exceptions!)
• each child of an affected parent has 50% risk to inherit each child of an affected parent has 50% risk to inherit trait.trait.
• unaffected family members do not transmit phenotype to unaffected family members do not transmit phenotype to children (exceptions again).children (exceptions again).
• males and females males and females equally likelyequally likely to transmit the trait, to to transmit the trait, to children of either sex. In particular, male-to-male children of either sex. In particular, male-to-male transmission does occur (in contrast to sex-linked transmission does occur (in contrast to sex-linked dominant inheritance).dominant inheritance).
• new mutationsnew mutations relatively common relatively common