Autosomal Dominant Disorders Flashcards
types of dominant mutations
loss of function through haploinsufficiency or dominant negative mutations
gain of function
haploinsufficiency
the level of product required for normal function might be so critical that the amount produced by a single functioning allele would be inadequate
ex. familial hypercholesterolemia - lack of LDL receptors
dominant negative effects
the abnormal protein interferes or competes with the normal function of the normal protein
ex. insulin Chicago - phenylalanine to leucine substitution causes mutant insulin to lose function but also bind to receptors and prevent regular insulin from binding, leads to hyperinsulinemic diabetes
five mutations that leads to familial hypercholesterolemia
gene deletion or decreased synthesis
impaired transport to Golgi
mutant receptors fail to bind LDL
failure of receptors to cluster in coated pits
impaiment of receptor recycling
types of dimer mutations that lead to dominant negative effects
mutation in one allele interferes with dimer association and interaction with other molecules
mutation where one allele increases affinity but results in decreased interaction with other molecules (>75% loss of function )
mutation in one allele results in 75% reduction in function by interfering with interaction with other molecules, despite that dimer association is normal
osteogenesis imperfecta
protein suicide - abnormality in either the pro-alpha1 or pro-alpha2 genes leads to improper formation or stability of the collagen, leading to rapid degradation in 3/4 different fiber compositions
phenomenon called protein suicide, leads to many bone deformities and weakenss
Classical Ehlers-Danlos Syndrome
defect in alpha-1 and 2 of type 5 collagen
some symptoms include delayed motor milestones, sofy and velvety skin that bruises easily, creates cigarette paper scars, hyperelastic and fragile
fleshy lesions, joint hypermobility, mitral valve prolapse, hiatial hernia, anal prolapse, pes planus (flat feet)
achondroplasia
characterized by small stature, disproportionate shortening of the proximal limb segments, short base of the skull with a large head, spinal stenosis, normal intelligence
caused by a single base substitution that results in a glycine to arginine mutation at position 380 of the gene product of the fibroblast growth factor receptor 3 (FGFR3), which constitutively represses chondrocyte proliferation
gain of function mutation
Wolf-Hirschhorn Syndrome (4p-)
deletion of terminal 4p, which inc ludes FGFR3, frowth deficiency, microcephaly, severe mental deficiency, hypertelorism, (widely spaced eyes), cleft lip and/or palate, micrognathia (small mandible)
haploinsufficiency, different from achondroplasia
familial male precocious puberty
sex-limited trait, causes early signs of puberty in males
due to mutation that leads to constitutive activation of the leuteinizing hormone receptor, which leads to increased testosterone production
gain of function mutation that leads to