title: Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital B289, Cambridge, CB2 0QR, UK.
authors.forename: E
authors.initials: E
authors.lastname: Raffan
authors.forename: M A
authors.initials: MA
authors.lastname: Soos
authors.forename: N
authors.initials: N
authors.lastname: Rocha
authors.forename: A
authors.initials: A
authors.lastname: Tuthill
authors.forename: A R
authors.initials: AR
authors.lastname: Thomsen
authors.forename: C S
authors.initials: CS
authors.lastname: Hyden
authors.forename: J W
authors.initials: JW
authors.lastname: Gregory
authors.forename: P
authors.initials: P
authors.lastname: Hindmarsh
authors.forename: M
authors.initials: M
authors.lastname: Dattani
authors.forename: E
authors.initials: E
authors.lastname: Cochran
authors.forename: J
authors.initials: J
authors.lastname: Al Kaabi
authors.forename: P
authors.initials: P
authors.lastname: Gorden
authors.forename: I
authors.initials: I
authors.lastname: Barroso
authors.forename: N
authors.initials: N
authors.lastname: Morling
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: R K
authors.initials: RK
authors.lastname: Semple
mesh_terms: D000328:Adult; D000349:Africa; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016133:Polymerase Chain Reaction; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D011498:Protein Precursors; C051512:insulin proreceptor; D011972:Receptor, Insulin