autosomal dominant disorders more than half of mendelian phenotypes are autosomal dominant ...
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Autosomal Dominant DisordersAutosomal Dominant Disorders
More than half of Mendelian phenotypes More than half of Mendelian phenotypes are autosomal dominantare autosomal dominant
Examples:Examples: Familial hypercholesterolemiaFamilial hypercholesterolemia Myotonic dystrophyMyotonic dystrophy Huntington diseaseHuntington disease NeurofibromatosisNeurofibromatosis Polycystic kidney diseasePolycystic kidney disease AchondroplasiaAchondroplasia
In typical AD inheritance, every affected In typical AD inheritance, every affected person in a pedigree has an affected person in a pedigree has an affected parentparent
This is also true for X-linked dominant This is also true for X-linked dominant traitstraits
Male-to-male transmission can readily Male-to-male transmission can readily distinguish AD phenotypes distinguish AD phenotypes
Autosomal Dominant DisordersAutosomal Dominant Disorders
Familial Familial hypercholesterolemiahypercholesterolemia
Familial hypercholesterolemiaFamilial hypercholesterolemia
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
+
New Mutation in AD DisordersNew Mutation in AD Disorders
New alleles arise by mutation and are New alleles arise by mutation and are maintained or removed by selectionmaintained or removed by selection
Survival of new mutation in the population Survival of new mutation in the population depends on the fitness of persons carrying depends on the fitness of persons carrying it as compared to persons with other it as compared to persons with other alleles at the locus concernedalleles at the locus concerned
Many autosomal dominant disorders are associated with reduced fitness
• 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
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.
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
Neurofibromatosis (NF1)-common disorder of the nervous system
1. Multiple benign fleshy tumors (neurofibromas) in the skin
Neurofibromatosis (NF1)-common disorder of the nervous system
2. Multiple flat, irregular pigmented skin lesions known as café au lait spots
Neurofibromatosis (NF1)-common disorder of the nervous system
3. Small benign tumors (hamartomas) on the iris of the eye
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
Reduced PenetranceReduced PenetranceExample: Split-hand deformity (lobster-claw Example: Split-hand deformity (lobster-claw
malformation) a type of ectrodactylymalformation) a type of ectrodactyly
This female is non-penetrant
Sex-dependent PenetranceSex-dependent Penetrance
Example: BRCA2 Familial Breast CancerExample: BRCA2 Familial Breast Cancer
Although men can get breast cancer, penetrance is much lower than in woman who inherit BRCA2 mutations
Age of Onset Age of Onset (age-dependent penetrance)(age-dependent penetrance)
Example: Huntington DiseaseExample: 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?
Possible Causes of incomplete Possible Causes of incomplete penetrancepenetrance
Genotypes do not act in isolationGenotypes do not act in isolation Interaction with the wild-type alleleInteraction with the wild-type allele Interaction with other lociInteraction with other loci Interaction with the environmentInteraction with the environment Not known!Not known!
Homozygotes for AD TraitsHomozygotes for AD Traits
Matings that could produce homozygous Matings that could produce homozygous offspring are rare (offspring are rare (A/a x A/aA/a x A/a, A/A x A/a or A/A x , A/A x A/a or A/A x A/A)A/A)
Disorders are usually more severe in Disorders are usually more severe in homozygoteshomozygotes
Example 1:Example 1: Achondroplasia: a skeletal disorder of short-limb Achondroplasia: a skeletal disorder of short-limb
dwarfism and large head sizedwarfism and large head size Marriage b/w achondroplastic (heterozygotes) is Marriage b/w achondroplastic (heterozygotes) is
commoncommon Homozygous achondroplastic patients are much more Homozygous achondroplastic patients are much more
severely affected & commonly do not survive early severely affected & commonly do not survive early infancyinfancy
AchondroplasiaAchondroplasia
Short limbs, a normal-sized head and Short limbs, a normal-sized head and body, normal intelligencebody, normal intelligence
Caused by mutation in the FGFR3 geneCaused by mutation in the FGFR3 gene
Fibroblast growth factor receptor 3Fibroblast growth factor receptor 3 Inhibits bone growth by inhibiting chondrocyte Inhibits bone growth by inhibiting chondrocyte
proliferation and differentiation proliferation and differentiation
Mutation causes the receptor to signal Mutation causes the receptor to signal even in absence of ligandeven in absence of ligand
extracellular
intracellular
Normal FGFR3 signalingNormal FGFR3 signaling
FGFR3FGFR3FGF ligandFGF ligand
extracellular
intracellular
Normal FGFR3 signalingNormal FGFR3 signaling
Inhibition of bone growthInhibition of bone growth
extracellular
intracellular
AchondroplasiaAchondroplasia
• Receptor signals in absence of ligandReceptor signals in absence of ligand• Bone growth attenuatedBone growth attenuated
Gly380Arg mutation in transmembrane domain
**
Example 2: Example 2: familial hypercholesterolemia, an AD familial hypercholesterolemia, an AD
disorder leading to premature coronary disorder leading to premature coronary heart diseaseheart disease
Homozygotes have a very severe disease Homozygotes have a very severe disease with much shorter life expectancy as with much shorter life expectancy as compared to heterozygotescompared to heterozygotes
Huntington DiseaseHuntington Disease
HD is a neurodegenerative disease HD is a neurodegenerative disease characterized by progressive dementia and characterized by progressive dementia and abnormal movementsabnormal movements
HD is an exception in that severity of the HD is an exception in that severity of the disorder (clinical expression) is the same in disorder (clinical expression) is the same in heterozygotes and homozygotes (onset age?)heterozygotes and homozygotes (onset age?)
HD homozygotes can be distinguished from HD homozygotes can be distinguished from heterozygotes by molecular analysis of mutant heterozygotes by molecular analysis of mutant genegene
Sex-Limited Phenotype in Autosomal DiseaseSex-Limited Phenotype in Autosomal Disease
Defect is autosomally transmitted but expressed Defect is autosomally transmitted but expressed in only one sexin only one sex
Example: Example: male-limited precocious pubertymale-limited precocious puberty (familial (familial
testotoxicosis), an AD disorder, affected boys testotoxicosis), an AD disorder, affected boys develop 2develop 2º sexual characteristics and adolescent º sexual characteristics and adolescent growth spurt at ~ 4 yrsgrowth spurt at ~ 4 yrs
In some families, mutation is in In some families, mutation is in leutinizing leutinizing hormone receptor genehormone receptor gene (mutant receptor signals (mutant receptor signals without hormone). without hormone).
The defect is non-penetrant in heterozygous The defect is non-penetrant in heterozygous females (another example of sex-dependent females (another example of sex-dependent penetrance) penetrance)
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.
• 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
Characteristics of Autosomal Dominant Characteristics of Autosomal Dominant DisordersDisorders