Autosomal recessive disorder Flashcards
recurrence risk for each unborn child of autosomal recessive disorders
1/4
chance of unaffected sibling being carrier
2/3
allelic heterogeneity
presence of multiple common mutant alleles of same gene in a population
ie: variations of beta globin proteins: beta^a, beta^s, beta^c
compound heterozygotes
an indiv who carries two different mutant alleles of same gene
ie: beta^delta, beta^c
PKU mutation in what gene? Resulting in what?
What is 2nd way indiv can develope PKU?
defect in PAH gene encoding phenylalanine hydroxylase (PAH) protein.
-mutation in genes encoding BH4 (PAH cofactor)
what mechanism does PKU defect interrupt?
Phe (F) —-PAH—> Tyr (Y)
PKU = high Phe level and low Tyr levels
Is PKU like sickle cell disease and have high allelic heterogeneity?
Yes
(7 mut alleles in European pop
6 mut alleles in Asian pop)
What is a BH4 supplementation used for treatment of PKU?
Kuvan
Name a newborn screening tech used for PKU
tandem mass spectrometry (MS/MS)
alpha-1 antitrypsin deficiency is early/late onset
late
alpha-1 antitrypsin deficiency
caused by what (2 ways)? and results in
1) mutation in a-1-AT (SERPINA) gene at Z allele (Glu342Lys)
- very low a-1-AT/SERPINA1 prot
- misfolded prot aggregation
2) mutation in a-1-AT (SERPINA) gene at S allele (Glu342Lys)
- decreased a-1-AT/SERPINA1 prot-> less effective
alpha-1 antitrypsin deficiency
clinical symptoms/phenotype
20x increased risk of emphysema
liver cirrhosis
increased rish of liver carcinoma
biological and environmental factors that play a role in alpha-1 antitrypsin deficiency
more common in people with northern ancestry
earlier and more severe in smokers
alpha-1 antitrypsin deficiency: mutation of SERPINA1 gene on which ch?
ch14q32.13
Mechanism at how smoking can contribute to damage of lungs in alpha-1 antitrypsin deficiency
tobacco smoke damages lungs -> more neutrophils released -> more elastase released-> more elastin degraded -> more severe lung damage
SERPINA1 function
suicide substrate that bind/inhibits serine proteases (elastase)
In alpha-1-antitrypsin deficiency, a mutation at which allele on the a-1-AT (SERPINA) gene is more dangerous/shows more disease symptoms?
Z allele (Glu342Lys)
- accounts for most cases of disease
- indiv with Z/Z genotype have ~15% of normal a-1-AT/SERPINA1 levels
- z allele encodes misfolded protein that aggregates in ER -> liver damage.
Tay-sachs diseases is what type of disease? Common in what type of population?
Lysosomal storage disease
ashkanazie jews
Tay-sachs diseases caused by what? Results in what?
mutation in Hex A gene -> defective hexosaminidase A protein- needed for GM2 metabolism in brain
-resulting in 300 fold accumulation of sphingolipid inside swollen lysosomes in neurones onf CNS
Hexosaminidase A consists of what subunits? Which subunit is defective in Tay sachs?
alpha and beta subunits
-alpha is defective - (due to Hex A gene mut)
Sandhoff disease,
which subunit is defective? Which gene(s) are defective?
Gm2 gangliosidosis type II
defective beta subunit
defect in both Hex A and Hex B
AB variant Tay Sachs
Both Hex A and Hex B normal, but GM2 acculm due to defect in GM2 activator protein (GM2AP)
-> cannot digest lipid -> build up GM2
