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. 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

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
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.

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

17. 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

18. 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?

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
Incomplete dominance

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. Normal FGFR3 signaling
FGF ligand
FGFR3
extracellular
intracellular

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

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