Journal Article

Genotype–phenotype correlation in inherited severe insulin resistance

Nicola Longo, Yuhuan Wang, Shelley A. Smith, Sharon D. Langley, Linda A. DiMeglio and Daniel Giannella-Neto

in Human Molecular Genetics

Volume 11, issue 12, pages 1465-1475
Published in print June 2002 | ISSN: 0964-6906
Published online June 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.12.1465
Genotype–phenotype correlation in inherited severe insulin resistance

Show Summary Details

Preview

The insulin receptor is a ligand-activated tyrosine kinase. Mutations in the corresponding gene cause the rare inherited insulin-resistant disorders leprechaunism and Rabson–Mendenhall syndrome. Patients with the most severe syndrome, leprechaunism, have growth restriction, altered glucose homeostasis and early death (usually before 1 year of age). Rabson–Mendenhall syndrome is less severe, with survival up to 5–15 years of age. These disorders are transmitted as autosomal recessive traits. Here we report six new patients and correlate mutations in the insulin receptor gene with survival. Patients with leprechaunism were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor and their cells had markedly impaired insulin binding (<10% of controls). Mutations in their insulin receptor gene inserted premature stop codons (E124X, R372X, G650X, E665X and C682X), resulting in decreased levels of mature mRNA, or affected the extracellular domain of the receptor (R86P, A92V, ΔN281, I898T and R899W). Three patients with Rabson–Mendenhall syndrome had at least one missense mutation in the intracellular domain of the insulin receptor (P970T, I1116T, R1131W and R1174W). Expression studies in CHO cells indicated that the R86P, A92V, ΔN281, I898T, R899W and R1131W mutations markedly impaired insulin binding (<5% of control), while the P970T, I1116T and R1174W mutant receptors retained significant insulin-binding activity. These results indicate that mutations in the insulin receptor retaining residual insulin-binding correlate with prolonged survival in our series of patients with extreme insulin resistance.

Journal Article.  8076 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.