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

TY - JOUR

T1 - Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling

AU - Raffan, E

AU - Soos, M A

AU - Rocha, N

AU - Tuthill, A

AU - Thomsen, Anni Rønfeldt

AU - Hyden, C S

AU - Gregory, J W

AU - Hindmarsh, P

AU - Dattani, M

AU - Cochran, E

AU - Al Kaabi, J

AU - Gorden, P

AU - Barroso, I

AU - Morling, N

AU - O'Rahilly, S

AU - Semple, R K

PY - 2011/5/1

Y1 - 2011/5/1

N2 - 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.

AB - 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.

KW - Adult

KW - Africa

KW - Cells, Cultured

KW - Child

KW - Female

KW - Haplotypes

KW - Humans

KW - Infant

KW - Insulin Resistance

KW - Male

KW - Mutagenesis, Site-Directed

KW - Mutation

KW - Polymerase Chain Reaction

KW - Protein Precursors

KW - Receptor, Insulin

KW - Young Adult

U2 - 10.1007/s00125-011-2066-z

DO - 10.1007/s00125-011-2066-z

M3 - Journal article

C2 - 21318406

SN - 0012-186X

VL - 54

SP - 1057

EP - 1065

JO - Diabetologia

JF - Diabetologia

IS - 5

ER -