Presentation on theme: "Autosomal Dominant Disorders"— Presentation transcript:
1 Autosomal Dominant Disorders More than half of Mendelian phenotypes are autosomal dominantExamples:Familial hypercholesterolemiaMyotonic dystrophyHuntington diseaseNeurofibromatosisPolycystic kidney diseaseAchondroplasia
2 In typical AD inheritance, every affected person in a pedigree has an affected parent This is also true for X-linked dominant traitsMale-to-male transmission can readily distinguish AD phenotypes
4 Familial hypercholesterolemia MaternalPaternalPunnett Square“a” = normal allele“A” = mutant allelePWhat is the probability that this pregnancy will be affected?Aa1/21/4affectedAaAaaa1/41/21/2+1/2+unaffected
5 New Mutation in AD Disorders New alleles arise by mutation and are maintained or removed by selectionSurvival of new mutation in the population depends on the fitness of persons carrying it as compared to persons with other alleles at the locus concernedMany 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 toreproduce--ex. Death by age of reproduction1 if the same ability to reproduce as gen. pop.If the fitness is 0, all affected individuals must be due to new mutationsIf the fitness is 1, i.e., the onset of the disorder isafter reproduction and therefore does not affect it, a patient is more likely to have inherited the disorderHaldane’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 FitnessAlways the Result of a New Mutation
9 Autosomal Dominant disorders frequently have differences in expression of mutant genesPenetrance: probability of any phenotypeall or none conceptExpressivity: severity of the phenotypein individuals with the samegenotypePleiotropy: a genetic defect results in diversephenotypic effectsExample: 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 ascafé 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 developmentof cancer of the NS or muscleAdult heterozygotes almost always demonstrate some signof the disease Penetrance is 100% but age-dependentPhenotype ranges from café au lait spots to tumors of thespinal cord Variable expressivityPleiotropic affects skin, iris, brain, muscle
14 Pedigree of a family with NF-1, apparently originating as a new mutation in the proband
15 Reduced PenetranceExample: Split-hand deformity (lobster-claw malformation) a type of ectrodactylyThis female is non-penetrant
17 Sex-dependent Penetrance Example: BRCA2 Familial Breast CancerAlthough 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 Disease803010025age in years% affected?What is the probability that she has inherited ahuntingtin mutationgiven that she's unaffected at 30?
19 Possible Causes of incomplete penetrance Genotypes do not act in isolationInteraction with the wild-type alleleInteraction with other lociInteraction with the environmentNot 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 homozygotesExample 1:Achondroplasia: a skeletal disorder of short-limb dwarfism and large head sizeMarriage b/w achondroplastic (heterozygotes) is commonHomozygous achondroplastic patients are much more severely affected & commonly do not survive early infancyIncomplete dominance
21 AchondroplasiaShort limbs, a normal-sized head and body, normal intelligence
22 Caused by mutation in the FGFR3 gene Fibroblast growth factor receptor 3Inhibits bone growth by inhibiting chondrocyte proliferation and differentiationMutation causes the receptor to signal even in absence of ligand
23 Normal FGFR3 signalingFGF ligandFGFR3extracellularintracellular
24 Normal FGFR3 signaling Inhibition of bone growth extracellular intracellularInhibition of bone growth
25 * Achondroplasia Receptor signals in absence of ligand Gly380Arg mutation intransmembrane domainextracellularintracellular*Receptor signals in absence of ligandBone growth attenuated
27 Example 2:familial hypercholesterolemia, an AD disorder leading to premature coronary heart diseaseHomozygotes have a very severe disease with much shorter life expectancy as compared to heterozygotes
28 Cutaneous xanthomas in a familial hypercholesterolemia homozygote.
29 Huntington DiseaseHD is a neurodegenerative disease characterized by progressive dementia and abnormal movementsHD 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 sexExample:male-limited precocious puberty (familial testotoxicosis), an AD disorder, affected boys develop 2º sexual characteristics and adolescent growth spurt at ~ 4 yrsIn 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 generationeach 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