Autosomal Dominant Disorders

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

2. 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

3. Autosomal Dominant Disorders Familial hypercholesterolemia

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

5. 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

6. 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

7. 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.

8. Hutchinson-Gilford Progeria • Autosomal Dominant, Zero Fitness • Always the Result of a New Mutation

9. 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

10. Neurofibromatosis (NF1)-common disorder of the nervous system 1. Multiple benign fleshy tumors (neurofibromas) in the skin

11. Neurofibromatosis (NF1)-common disorder of the nervous system 2. Multiple flat, irregular pigmented skin lesions known as café au lait spots

12. Neurofibromatosis (NF1)-common disorder of the nervous system 3. Small benign tumors (hamartomas) on the iris of the eye

13. 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

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

15. This female is non-penetrant Reduced Penetrance Example: Split-hand deformity (lobster-claw malformation) a type of ectrodactyly

17. Although men can get breast cancer, penetrance is much lower than in woman who inherit BRCA2 mutations Sex-dependent Penetrance Example: BRCA2 Familial Breast Cancer

18. 100 % affected 25 ? 0 30 80 age in years What is the probability that she has inherited a huntingtin mutation Age of Onset (age-dependent penetrance) Example: Huntington Disease given that she's unaffected at 30?

19. 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!

20. 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

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

22. 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

23. extracellular intracellular Normal FGFR3 signaling FGF ligand FGFR3

24. extracellular intracellular Normal FGFR3 signaling Inhibition of bone growth

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

27. 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

28. Cutaneous xanthomas in a familial hypercholesterolemia homozygote.

29. 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

30. 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)

31. 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.

32. 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