Autosomal Dominant Disorders More than half of Mendelian phenotypes are autosomal dominant Examples: Familial hypercholesterolemia Myotonic dystrophy Huntington disease Neurofibromatosis Polycystic kidney disease Achondroplasia

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

Autosomal Dominant Disorders Familial hypercholesterolemia

Familial hypercholesterolemia Maternal Paternal Punnett Square “a” = normal allele “A” = mutant allele P What is the probability that this pregnancy will be affected? A a 1/2 1/4 affected Aa Aa aa 1/4 1/2 1/2 + 1/2 + unaffected

New Mutation in AD Disorders 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

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 Haldane’s Rule: Since the incidence of a disease remains constant over time, then the mutant alleles lost because of reduced fitness must be balanced by alleles arising from new mutation.

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 Penetrance: probability of any phenotype all or none concept Expressivity: severity of the phenotype in individuals with the same genotype 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 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 sign of 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 Penetrance Example: Split-hand deformity (lobster-claw malformation) a type of ectrodactyly This female is non-penetrant

Sex-dependent Penetrance Example: 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-dependent penetrance) Example: Huntington Disease 80 30 100 25 age in years % affected ? What is the probability that she has inherited a huntingtin mutation given that she's unaffected at 30?

Possible Causes of incomplete penetrance Genotypes do not act in isolation Interaction with the wild-type allele Interaction with other loci Interaction with the environment Not known!

Homozygotes for AD Traits 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 Incomplete dominance

Achondroplasia Short limbs, a normal-sized head and body, normal intelligence

Caused by mutation in the FGFR3 gene 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

Normal FGFR3 signaling FGF ligand FGFR3 extracellular intracellular

Normal FGFR3 signaling Inhibition of bone growth extracellular intracellular Inhibition of bone growth

* Achondroplasia Receptor signals in absence of ligand Gly380Arg mutation in transmembrane domain extracellular intracellular * Receptor signals in absence of ligand Bone growth attenuated

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

Cutaneous xanthomas in a familial hypercholesterolemia homozygote.

Huntington Disease 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

Sex-Limited Phenotype in Autosomal Disease 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)

Pedigree pattern of male-limited precocious puberty 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.

Characteristics of Autosomal Dominant Disorders phenotype appears in every generation each affected person has an affected parent (exceptions!) each child of an affected parent has 50% risk to inherit trait. unaffected family members do not transmit phenotype to children (exceptions again). males and females equally likely to transmit the trait, to children of either sex. In particular, male-to-male transmission does occur (in contrast to sex-linked dominant inheritance). new mutations relatively common