1.2 Autosomal Dominant Flashcards
(52 cards)
Autosomal Dominant mutations
usually affects structural proteins or ones with complex functions –> making more wont help (rate limiting proteins), not single enzymes
AD with toxic abnormal gene product
gain of function – Huntington disease
AD with abromal product that interferes with other normal proteins
dominant negative
What autosomal dominant conditions is associated with young athletes that die?
Hypertrophic Cardiomyopathy – freq of 1/500 so it would be beneficial to screen for this and prevent fatality
Familial Hyercholesteremia
AD disease where there is structural alteration in LDL receptor—-remember that this is the name of this specific disease bc there are other hypercholesterolemias that are familial but are not this!
what is the most frequent mandelian disorder
familial hypercholesteremia – 1:500 heterozygous for FH
where is the gene located for familial hypercholesterolemia
chromosome 19 and it is an extremely large gene so it_s a big gene target
identified mutations in familial hypercholesterolemia
900 identified – alterations include failure to synthesize receptor, inability to bind LDL, inability to internalize receptor, inability to disassociate LDL
in FH there is inc in cholesterol bc
of dec in clearance and dec in feed back mechanisms stimulating inc synthesis of cholesterol
How does FH work wrt the liver
the LDL receptors on the liver don’t exist so the LDL that is present is not getting into the liver cell, so now the liver cell thinks there is low cholesterol and starts to synthesize more cholesterol. Normally that LDL getting into the cell via the receptor is going to inhibit HMG-coA reductase so there will be inhibition of synthesis bc the cell is like –hey we’ve got cholesterol stop making more.
clearance of cholesterol
only if the LDL receptor exists on the liver cell can it get in and then be put into VLDL that are then cleared by lypolysis in circulation
Clinical course of heterozygous FH
2-3 fold inc in serum cholestorol, inc rates of ACVD. See xanthomas on eyelids and flexor tendons – serum will be milky white
clinical course of homozygous FN
massive inc in serum cholesterol, can have MI in teens or <30yo — serum will be milky white bc of all the excess fat
grey around iris
high cholesterol
statins in normal ppl
don_t really lower cholesterol but they do have a lower rate of heart attack and it is thougt that statins also have antiinflammatory capacity
Marfan syndrome
autosomal dominant – generalized elastic tissue defect –>hyperflexible joints, aortic aneurysms, mitral valve prolapse
Even though Marfan’s syndrom is a generalized elastic tissue defect, it is not a mutation in elastin. Instead
Fibrilin -1 is the gene
fibrilin 1 mutations in Marfan’s
> 500 mutations mostly missense, mutations in fibrillin-1 gene–> have abnormal protein that impairs microfibril assembly; microfibrils are scaffold for elastic fibers–>DOMINANT NEGATIVE
de novo/sporadic cases of disease
are mostly seen in AD diseases but not AR diseases
sporadic cases of Marfan’s
03-Jan
what outcome does Marfan’s have on young athletes
sudden death
characteristic features of Marfans
tall, thin, and long extremities, fingers, and toes; height unbalanced and contributed by long legs; hyper flexible joints; dilichocephalic with prominent supraorbital ridges (Abraham Lincolm); Dislocation of lenses (ectopia lentis). Rare and practically diagnostic; Mitral valve prolapse; dialation of aortic ring; Aortic insufficiency; Dissecting aneurysms(called aortic aneurysms now); variable expression (different mutations); major involvement in 2 of 4 organ systems and minor of 1 (skeletal, cardiovascular, skin, ocular)
Aortic dissections in Marfan’s
get an intimal tear. Aorta has natural dissection planes bc there is so much longitudinal and circular muscle. When you have a tear, blood leaks out pushes inward
Causes of sudden death
heart attack, stroke, ruptured saccular aneurysm, dissecting aneyrysm
