Human Molecular Genetics, 2002, Vol. 11, No. 12 1465-1475
© 2002 Oxford University Press
Genotype–phenotype correlation in inherited severe insulin resistance
1Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA, 2Division of Medical Genetics, Department of Pediatrics, Emory University, Atlanta, GA, USA, 3Department of Pediatrics, Section of Pediatric Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, IN, USA and 4Laboratory for Cellular and Molecular Endocrinology, Division of Endocrinology, University of São Paulo School of Medicine, São Paulo, Brazil
Received February 27, 2002; Accepted March 27, 2002
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, 
N281, 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, N281, 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.
* To whom correspondence should be addressed at: Division of Medical Genetics, Department of Pediatrics, University of Utah, 2C412 SOM, 50 North Medical Drive, Salt Lake City, UT 84103, USA. Tel: +1801 587 9071; Fax: +1801 585 0956; Email: Nicola.Longo{at}hsc.utah.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Torkamani, N. Kannan, S. S. Taylor, and N. J. Schork Congenital disease SNPs target lineage specific structural elements in protein kinases PNAS, July 1, 2008; 105(26): 9011 - 9016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J R Porter and T G Barrett Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and {beta} cell failure J. Med. Genet., December 1, 2005; 42(12): 893 - 902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Park, D. K. Jin, S. M. Shin, M. K. Jang, N. Longo, J. W. Park, D. S. Bae, and Y. S. Bae Impaired Generation of Reactive Oxygen Species in Leprechaunism Through Downregulation of Nox4 Diabetes, November 1, 2005; 54(11): 3175 - 3181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J R Porter and T G Barrett Acquired non-type 1 diabetes in childhood: subtypes, diagnosis, and management Arch. Dis. Child., December 1, 2004; 89(12): 1138 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kajantie, T. Hytinantti, P. Hovi, and S. Andersson Cord Plasma Adiponectin: A 20-Fold Rise between 24 Weeks Gestation and Term J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4031 - 4036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Cochran, J. R. Young, N. Sebring, A. DePaoli, E. A. Oral, and P. Gorden Efficacy of Recombinant Methionyl Human Leptin Therapy for the Extreme Insulin Resistance of the Rabson-Mendenhall Syndrome J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1548 - 1554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. McCarthy Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification Hum. Mol. Genet., April 1, 2004; 13(suppl_1): R33 - R41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Maassen, E. S. Tobias, H. Kayserilli, T. Tukel, M. Yuksel-Apak, E. d'Haens, W. J. Kleijer, F. Fery, and G. C. M. van der Zon Identification and Functional Assessment of Novel and Known Insulin Receptor Mutations in Five Patients with Syndromes of Severe Insulin Resistance J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4251 - 4257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. George, A. Johansen, M. A. Soos, H. Mortensen, S. Gammeltoft, V. Saudek, K. Siddle, L. Hansen, and S. O'Rahilly Deletion of V335 from the L2 Domain of the Insulin Receptor Results in a Conformationally Abnormal Receptor That Is Unable to Bind Insulin and Causes Donohue's Syndrome in a Human Subject Endocrinology, February 1, 2003; 144(2): 631 - 637. [Abstract] [Full Text] [PDF]
|
|