1-22 Autosomal Dominant Disorders

Question 1

Types of dominant mutations

Answer 1

loss of fxn:
-haploinsuffienciencey (expect 50% of gene product, if this is pathologic we call in haploinsuff)
-dominant negative (one bad allele masks the healthy allele)
+protein suicide

gain of fxn:

Question 2

Familial hypercholesterolemia

Answer 2

ex. haploinsufficiency dominant mutations

LDL receptors normally bind LDL and internalize into cell, in FH if there is a mutation that gives half the amount of LDL receptors which causes a dominant phenotype of hypercholesteralemia

homozygote mutants have basically no recpetors and super super high cholesterol, dose response of chol level to LDL receptor level

Question 3

Insulin Chicago

Answer 3

rare cause of diabetes, related to mutations in insulin gene

proinsulin normally has a few di-sulfide bonds in peptide, in a point mutations of Phe to Leu, produces diabetes, this insulin chain no longer works like insulin to promote glucose uptake in to cells but still binds to insulin receptor, so is basically a competitive inhibitor

DOMINANT NEGATIVE, greater reduction in function than you would expect if this was just a haploinsufficient mutant

ex. if a dimer, and one allele produces mutant then three options: 2 healthy, 1 healthy 1 unhealthy, 1 unhealhty 1 healthy, 2 unhealthy, therefore only 1 of 4 options will be ableto bind receptor and function properly giving greater than 50% reduction in protein function

Question 4

Collagens (autosomal dominant conditions)

Answer 4

Extracellular proteins imporatn connective tissues, many types of collages/forms

made of triple helix (spontaneously form) with 1 alpha1chains (encoded by COLXA1) and 1 alpha2 chain (encoded by COLXA2), lots of PTMs

collagen fibril: made of many triple helices

Osteogenesis Imperfecta: muts which result in reduced synthesis or early degrade of procollagen (haploinsuff) result in: decreased mature collagen, collagen has normal structure therefore MILD PHENOTYPE; AA substitiuition/deletions that later the structure of procollagen may: exert a dominant negative effect OR alter the properties of mature callagen: SEVERE PHENOTYPE

Severe phenotype of mutated procollagen causes PROTEIN SUICIDE

Perinatal lethal if severe
Eye sclera blue

Question 5

Protein suicide

Answer 5

ex. osteogeneisi imperfecta, a mutant mal-formed procollagen chain will disrupt the triple helix marking any that incorporate the mutant for degredation

Question 6

Classical Type Ehlers-Danlos SYndrome

Answer 6

dominant, inherited

hyper-elastic connective tissue

mutations in type 5 collagen in alpha1 or alpha2 chains

most generate null alleles so no protein made and result in haploinsufficiency

Question 7

Achondroplasia

Answer 7

dominant, inherited

small stature, disproportionate shortening of proximal limb (upper arm/thigh), large head, spinal stenosis, normal intelligence

patients have GLY to ARG within the FGFR3, causes the receptor to function as if the ligand was bound leading to constitutive activation of bone growth: GAIN OF FUNCTION, protein has taken on a new fxn

Haploinsufficiency for FGFR3 DOES NOT cause achondroplasia

Question 8

Wolf-hirschorn syndrome

Answer 8

dominant, no inherited because folks cannot reproduce

deletions of 4p, including the FGFR3 gene therefore only 1 copy of FGFR3 (and other 4p genes)

growth deficiency, microcephaly, mental deficiency, hypertelorism, cleft lip/palate, micrognathia (small mandible)

Question 9

Familial Male precocious puberty

Answer 9

dominant, inherited

only males affected, male to male transmission, but also some with “no affected parent” if the parent is female

autosomal dominant sex limited trait

Receptor defect for lutinizing hormone (LH):

• normally: g-protein coupled receptor, normally when ligand binds receptor a site in G protein opened so can bind to ATP and form cAMP
• disease state: Receptor abnormal and g-protein will form cAMP even without binding of ligand to receptor, constititively active and leads to early puberty in boys

does not affect girls because this mechanism/pathway is not what triggers puberty in them

Question 10

Osteogenesis Imperfecta

Answer 10

muts which result in reduced synthesis or early degrade of procollagen (haploinsuff) result in: decreased mature collagen, collagen has normal structure therefore MILD PHENOTYPE; AA substitiuition/deletions that later the structure of procollagen may: exert a dominant negative effect OR alter the properties of mature callagen: SEVERE PHENOTYPE

Severe phenotype of mutated procollagen causes PROTEIN SUICIDE

Perinatal lethal if severe
Eye sclera blue