ï‚¨ more than half of mendelian phenotypes are autosomal dominant ï‚¨...
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More than half of Mendelian phenotypes are autosomal dominantExamples:Familial hypercholesterolemiaMyotonic dystrophyHuntington diseaseNeurofibromatosisPolycystic kidney disease**Achondroplasia--------------------------------------------------------** Less common AR form exisits
In typical AD inheritance, every affected person in a pedigree has an affected parentThis is also true for X-linked dominant traitsMale-to-male transmission can readily distinguish AD phenotypes
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
Fitness-probability of transmitting ones 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 Reported to occur in 1 in 4 million newborns worldwide
Autosomal Dominant disorders frequently have differences in expression of mutant genesPenetrance: 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 effectsExample: Neurofibromatosis
Neurofibromatosis (NF1)-common disorder of the nervous system1. Multiple benign fleshy tumors (neurofibromas) in the skinNeurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people worldwide
Neurofibromatosis (NF1)-common disorder of the nervous system2. Multiple flat, irregular pigmented skin lesions known as caf au lait spots
Neurofibromatosis (NF1)-common disorder of the nervous system3. Small benign tumors (hamartomas) on the iris of the eye
Neurofibromatosis (NF1)-common disorder of the nervous systemLess frequently, mental retardation, CNS tumors, diffuse plexiform neurofibormas and the development of cancer of the NS or muscleAdult heterozygotes almost always demonstrate some signof the disease Penetrance is 100% but age-dependent
Phenotype ranges from caf 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
Example: Split-hand deformity (lobster-claw malformation) a type of ectrodactyly
Example: BRCA2 Familial Breast Cancer
Example: Huntington Diseasegiven that she's unaffected at 30?
Genotypes do not act in isolationInteraction with the wild-type alleleInteraction with other lociInteraction with the environmentNot known!
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 infancy
Short limbs, a normal-sized head and body, normal intelligence
Fibroblast growth factor receptor 3Inhibits bone growth by inhibiting chondrocyte proliferation and differentiation
Mutation causes the receptor to signal even in absence of ligand
Normal FGFR3 signalingFGFR3FGF ligand
Normal FGFR3 signalingInhibition of bone growth
Achondroplasia Receptor signals in absence of ligand Bone growth attenuatedGly380Arg mutation in transmembrane domain*
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
Cutaneous xanthomas in a familial hypercholesterolemia homozygote.
HD 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
Defect is autosomally transmitted but expressed in only one sexExample: male-limited precocious puberty (familial testotoxicosis), an AD disorder, affected boys develop 2 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)
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 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
Of the 10,000 genetic traits and diseases currently known, more than half are autosomal-dominant.****Haldanes 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.
*Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance including prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears. Hutchinson-Gilford progeria syndrome also causes hair loss (alopecia), aged-looking skin, joint abnormalities, and a loss of fat under the skin (subcutaneous fat). This condition does not disrupt intellectual development or the development of motor skills such as sitting, standing, and walking.People with Hutchinson-Gilford progeria syndrome experience severe hardening of the arteries (arteriosclerosis) beginning in childhood. This condition greatly increases the chances having a heart attack or stroke at a young age. These serious complications can worsen over time and are life-threatening for affected individuals.Mutations in the LMNA gene cause Hutchinson-Gilford progeria syndrome.The LMNA gene provides instructions for making a protein called lamin A. This protein plays an important role in determining the shape of the nucleus within cells
***The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor. it keeps cells from growing and dividing too rapidly or in an uncontrolled way.****Five different genetic mutations are known to be associated with SHFM. Type I, the most frequent variety, is due to a mutation on chromosome 7 in a region that contains two homeobox genes, DLX5 and DLX6***Incomplete dominance**