Unit 2b Flashcards
WAGR Syndrome
Wilms tumor, aniridia, genitourinary malformations, intellectual disability
Genetics of WAGR
interstitial 11p13 deletion
-dx with high resolution chromosomal analysis and FISH for PAX6
Hereditary Neuropathy with liability to Pressure Palsies (HNPP)
due to deletion of
PMP22 gene leading to a phenotype where patients have temporary (usually reversible)
neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if
left in a certain position, these patients are more sensitive to pressure on nerves and their
limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
Osteogenesis Imperfecta Type 1
Loss of Function:
Nonsense (stop) mutations / frameshift mutations in
COL1A1 premature termination. Reduced amount of normal COL1A1 (collagen) protein
causing a ‘milder’ form of osteogenesis imperfect. Clinically characterized by increased
fractures, brittle bones, and blue sclera.
Hemoglobin Kempsey
Gain of Function:
(Beta hemoglobin gene, Asp99Asn missense mutation): leads to a hemoglobin molecule which has higher than normal oxygen affinity, and is less able to unload oxygen in the tissues.
Achondroplasia
FGFR3 Gly380Arg mutation increases the
normal signaling though intracellular tyrosine kinase domain (essentially having the receptor
constitutively in the ‘turned-on’ state).
Charcot Marie Tooth
due to duplication of PMP22 gene
also implicted in HNPP above) which leads to elevated PMP22 protein (component of myelin sheath
Loss of Function inheritance
typically recessive (one wt copy can usually rescue it)
Gain of function inheritance
Gain of function mutations caused by missense are often autosomal dominant (1 improper copy can perform the incorrect function)
Huntington Disease
Novel Property:
A triplet repeat disorder where by expansion of CAG
repeat ‘triplets’ in the gene increase the number of glutamine residues (the CAG codon codes
for glutamine). Increased polyglutamine residues above a certain threshold leads to a novel
toxic effect on the huntingtin protein
Heterochronic expression mutations
HFPH, some cancers
Trinucleotide expansions in non-coding regions (loss of function)
Fragile X, Friedrich Ataxia (mRNA not made, protein not made)
Trinucleotide expansions in noncoding regions (novel properties to RNA)
Myotonic Dystrophy, FXTAS (mRNA made but abnormal, protein not made)
Trinucleotide expansion in coding regions
Huntington disease, Spinocerebellar ataxia
Huntington Expansion
Paternal
