Clinical Applications

Question 0

Sherman paradox

Answer 0

Higher incidence of FRAXA in sons than uncles

Means Anticipation

Huntingtons disease also has anticipation with CAG repeats but it results in mutant enzyme with gain of function

Question 1

Fragile X syndrome (FRAXA)

Answer 1

X-linked dominant with reduced penetrance
Long face, broad forehead, progressive
Expansion of CGG triplet repeat in 1st exon, deactivation of protein via methylation of EagI site on FMR1 gene
More copy # means more severe disease, more expansion
Full blown FRAXA (>200 repeats) inherited from carrier mothers
Southern: carrier female has 4 bands (Normal methylated 5.2kb and normal nonmethylated 2.8kb, mutant methylated 5.5kb and mutant unmethylated 3.1kb), smears for mutant bands
Male (normal 2.8kb and mutated is 3.1kb) they have only one X that is always unmethylated (active) unless FRAXA
Heavier, larger band size from increase of CGG repeats

Question 2

Normal transmitting males

Answer 2

Actually may have mild symptoms like fragile-x-associated tremor or Ataxia syndrome later in life

Female carriers may have premature ovarian failure

Question 3

Sickle cell disease

Answer 3

Point mutation in codon 6 of B-globin gene
Carrier are a symptomatic, resistant to malaria
Homozygous have disease, hemolyticanemia

Question 4

B thalassemia

Answer 4

Less beta globin chain production via more than 100 point mutations (allelic heterogeneity)
Leads to excessive alpha chains, Heinz bodies (4 alphas) get destroyed
Major=homozygous, no beta; minor=carriers

Question 5

Alpha thalassemia

Answer 5

Less alpha globin chains
Creates beta globin clusters which don’t release oxygen
Homozygous deletions result in hydrops fetalis in SE Asia

Question 6

Cystic fibrosis

Answer 6

Autosomal recessive

Chronic pulmonary disease, pancreatic insufficiency, sweat chloride (defect in CFTR gene for chloride channels