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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling
Diabetologia, Volume 54, No. 5, Year 2011
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Description
Aims/hypothesis: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients 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 patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, 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 patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to β subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. Conclusions/interpretation: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients 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. © The Author(s) 2011.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3071941/bin/125_2011_2066_MOESM1_ESM.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3071941/bin/125_2011_2066_MOESM2_ESM.pdf
Authors & Co-Authors
Raffan, Eleanor
United Kingdom, Cambridge
University of Cambridge
Soos, Maria A.
United Kingdom, Cambridge
University of Cambridge
Rocha, Nuno M.
United Kingdom, Cambridge
University of Cambridge
Tuthill, Antoinette
United Kingdom, Cambridge
University of Cambridge
Thomsen, Anni R.
Denmark, Copenhagen
Det Sundhedsvidenskabelige Fakultet
Hyden, Caroline S.S.
United Kingdom, Cambridge
University of Cambridge
Gregory, John W.
United Kingdom, Cardiff
Cardiff University
Hindmarsh, Peter Christopher
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Dattani, Mehul Tulsidas
United Kingdom, London
Ucl Great Ormond Street Institute of Child Health
Cochran, Elaine K.
United States, Bethesda
National Institute of Diabetes and Digestive and Kidney Diseases Niddk
Al-Kaabi, Juma M.
United Arab Emirates, Al Ain
United Arab Emirates University
Gorden, Phillip
United States, Bethesda
National Institute of Diabetes and Digestive and Kidney Diseases Niddk
Barroso, Inês E.
United Kingdom, Cambridge
University of Cambridge
United Kingdom, Hinxton
Wellcome Sanger Institute
Morling, Niels
Denmark, Copenhagen
Det Sundhedsvidenskabelige Fakultet
O'Rahilly, Stephen P.
United Kingdom, Cambridge
University of Cambridge
Semple, Robert K.
United Kingdom, Cambridge
University of Cambridge
Statistics
Citations: 16
Authors: 16
Affiliations: 7
Identifiers
Doi:
10.1007/s00125-011-2066-z
ISSN:
0012186X
e-ISSN:
14320428
Research Areas
Cancer
Genetics And Genomics
Health System And Policy