Autosomal recessive disorder

Question 1

recurrence risk for each unborn child of autosomal recessive disorders

Answer 1

1/4

Question 2

chance of unaffected sibling being carrier

Answer 2

2/3

Question 3

allelic heterogeneity

Answer 3

presence of multiple common mutant alleles of same gene in a population

ie: variations of beta globin proteins: beta^a, beta^s, beta^c

Question 4

compound heterozygotes

Answer 4

an indiv who carries two different mutant alleles of same gene

ie: beta^delta, beta^c

Question 5

PKU mutation in what gene? Resulting in what?

What is 2nd way indiv can develope PKU?

Answer 5

defect in PAH gene encoding phenylalanine hydroxylase (PAH) protein.

-mutation in genes encoding BH4 (PAH cofactor)

Question 6

what mechanism does PKU defect interrupt?

Answer 6

Phe (F) —-PAH—> Tyr (Y)

PKU = high Phe level and low Tyr levels

Question 7

Is PKU like sickle cell disease and have high allelic heterogeneity?

Answer 7

Yes
(7 mut alleles in European pop
6 mut alleles in Asian pop)

Question 8

What is a BH4 supplementation used for treatment of PKU?

Answer 8

Kuvan

Question 9

Name a newborn screening tech used for PKU

Answer 9

tandem mass spectrometry (MS/MS)

Question 10

alpha-1 antitrypsin deficiency is early/late onset

Answer 10

late

Question 11

alpha-1 antitrypsin deficiency

caused by what (2 ways)? and results in

Answer 11

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

Question 12

alpha-1 antitrypsin deficiency

clinical symptoms/phenotype

Answer 12

20x increased risk of emphysema
liver cirrhosis
increased rish of liver carcinoma

Question 13

biological and environmental factors that play a role in alpha-1 antitrypsin deficiency

Answer 13

more common in people with northern ancestry

earlier and more severe in smokers

Question 14

alpha-1 antitrypsin deficiency: mutation of SERPINA1 gene on which ch?

Answer 14

ch14q32.13

Question 15

Mechanism at how smoking can contribute to damage of lungs in alpha-1 antitrypsin deficiency

Answer 15

tobacco smoke damages lungs -> more neutrophils released -> more elastase released-> more elastin degraded -> more severe lung damage

Question 16

SERPINA1 function

Answer 16

suicide substrate that bind/inhibits serine proteases (elastase)

Question 17

In alpha-1-antitrypsin deficiency, a mutation at which allele on the a-1-AT (SERPINA) gene is more dangerous/shows more disease symptoms?

Answer 17

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.

Question 18

Tay-sachs diseases is what type of disease? Common in what type of population?

Answer 18

Lysosomal storage disease

ashkanazie jews

Question 19

Tay-sachs diseases caused by what? Results in what?

Answer 19

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

Question 20

Hexosaminidase A consists of what subunits? Which subunit is defective in Tay sachs?

Answer 20

alpha and beta subunits

-alpha is defective - (due to Hex A gene mut)

Question 21

Sandhoff disease,

which subunit is defective? Which gene(s) are defective?

Answer 21

Gm2 gangliosidosis type II
defective beta subunit
defect in both Hex A and Hex B

Question 22

AB variant Tay Sachs

Answer 22

Both Hex A and Hex B normal, but GM2 acculm due to defect in GM2 activator protein (GM2AP)

-> cannot digest lipid -> build up GM2