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.

Hutchinson-Gilford Progeria

• Autosomal Dominant, Zero Fitness• Always the Result of a New Mutation

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

Pedigree of a family with NF-1, apparently originating as a new mutation in the proband

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

Cutaneous xanthomas in a familial hypercholesterolemia homozygote.

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