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Identification and Functional Assessment of Novel and Known Insulin Receptor Mutations in Five Patients with Syndromes of Severe Insulin Resistance

Department of Molecular Cell Biology (J.A.M., G.C.M.V.D.Z.), Leiden University Medical Centre, 2333 AL Leiden, the Netherlands; Department of Endocrinology (J.A.M.), Vrije Universiteit Amsterdam and Department of Pediatrics (E.D.), Vrije Universiteit-Medisch Centrum, 1007 MB Amsterdam, the Netherlands; Duncan Guthrie Institute of Medical Genetics (E.S.T.), Yorkhill NHS Trust, G61 1BD Glasgow, United Kingdom; Institute of Child Health (H.K., T.T., M.Y.-A.), University of Istanbul, 34390 Istanbul, Turkey; Department of Clinical Genetics (W.J.K.), Erasmus Medical Centre, 3015 GE Rotterdam, the Netherlands; and Hopital Erasme (F.F.), Universite Libre de Bruxelles, B-1070 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. J. A. Maassen, Department of Molecular Cell Biology, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands. E-mail: j.a.maassen{at}lumc.nl.

We analyzed the insulin receptor gene in four patients with leprechaunism and one with type A insulin resistance. We detected novel and previously reported mutations. The novel mutants were expressed in Chinese hamster ovary cells to evaluate the consequences for insulin receptor function. A type A insulin resistance patient from Morocco was homozygous for Arg252His mutation, similar to a previously described type A patient from Japan. A patient with leprechaunism was homozygous for the Ser323Leu mutation, previously identified in homozygous form in two patients with Rabson-Mendenhall syndrome. Phenotypic expression of this mutation is variable. A patient with leprechaunism is compound heterozygous for the previously described Arg1092Trp mutation and a nonsense mutation in codon 897. Another patient with leprechaunism was homozygous for a novel Asn431Asp mutation, which only partially reduces insulin proreceptor processing and activation of signaling cascades. The novel Leu93Gln mutation that fully disrupts proreceptor processing was found in one allele in a patient with leprechaunism. A nonsense mutation at codon 1122 was in the other allele. These results expand the number of pathogenic insulin receptor mutations and demonstrate the variability in their phenotypic expression. The biochemical analysis of mutant insulin receptors does not reliably predict whether the phenotype will be leprechaunism, the Rabson-Mendenhall syndrome, or type A insulin resistance. The previously reported correlation between fibroblast insulin binding and duration of patient survival was not observed.

This work was supported by grants from the Diabetes Fonds Nederland and the EU-COST B17 action.

Abbreviations: CHO, Chinese hamster ovary; 3D, three-dimensional; IRS-1, insulin receptor substrate.

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