Founder effect in the Horn of Africa for an XXXX mutation that may impair receptor recycling.

@entity1 @entity73118 @entity101 @entity4785 @entity8277
AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the @entity73118 missense mutation in the @entity8277 @entity8277 gene, previously reported in a Yemeni kindred, in four unrelated @entity1 with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected @entity1 were performed. @entity8277 expression in lymphoblastoid cells from a homozygous @entity73118 @entity8277 @entity1 , and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All @entity1 had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the @entity8277 mutant to be no larger than 28 kb. An @entity101 proreceptor to b subunit ratio was seen in @entity1 -derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited @entity4785 rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The @entity73118 @entity8277 appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant @entity1 with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only.
