Inborn Errors of Metabolism
Alkaptonuria (Garrod 1902) (OMIM
citation
203500)
Homogentisic Acid (formerly alkapton) accumulates in urine black
diapers
dark (ochronic) pigment
deposited in cartilage of nose & ears
Alkaptonuria
is a defect of Homogentisic Acid
Oxidase
Homogentisic Acid
accumulates in urine, blood, & cartilage
phenotype results from build-up of
substrates: not life-threatening
[Alkaptonuria provides an excellent
example of Ascertainment Bias in human
genetics]
Defective of tyrosinase in melanocytes
tyrosinase in
other organs unaffected (separate locus)
Sickle
Cell Anemia (Neel & Beet 1949) (OMIM
citation
603903)
Defect of beta-globin subunit of
hemoglobin tetramer
recall: two alpha + two beta chains
One beta-chain
allele inherited from each parent
protein
tetramers occur in ratio 1 MM : 2 FM : 1
FF [M = Mother, F = Father]
Both
alleles are expressed in molecular
phenotype:
call this "co-dominant"
expression
Standard hemoglobin has standard allele (A)
for beta chain
Alternative
allele (S) when homozygous (SS) produces sickle-cell anemia
crystallization of hemoglobin molecule as parallel fibers
& consequent
"sickling" of
red blood cells at low [O2]
causes
an infarctive crisis
pleiotropic effects include anemia &
skeletal anomalies
Heterozygotes
(AS) show "sickle-cell trait": mild anemia
25% of hemoglobins are SS: AA & AS tetramers don't crystallize readily
Both alleles are expressed in disease phenotype
[A mutation of the
primary beta-globin gene DNA
sequence]
Huntington
Disease
(AKA Huntington's Chorea) (OMIM
citation
143100)
Progressive, degenerative neural disorder; uncontrolled ("choreic") movements
Late onset: first symptoms may not appear until after
child-bearing years
Biochemical
indications ambiguous in early stages
A
genetic counseling
ethical dilemma:
Tiresias'
Dilemma: 'It is but sorrow to be wise when
wisdom profits not.'
Very common
in some pedigrees
huntingtin protein [sic]
has extra Gln residues at N-terminus
due
to poly-CAG at 5' end of gene
poly-glutamine
tract forms plaques on Central Nervous System
Phenotypic effect is a consequence of the presence of huntingtin [sic]
protein
in homozygotes and heterozygotes,
irrespective of standard protein
Huntington Disease therefore
shows dominant expression:
Alleles
with poly-CAG tract
dominate expression of non-poly-CAG alleles
(Woody
Guthrie had it: some of his tunes;
Last thoughts
on Woody Guthrie by Bob Dylan)
All text material ©2016 by Steven M. Carr