Diabetes, Vol 43, Issue 2 247-255, Copyright © 1994 by American Diabetes Association

ARTICLES

Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance

DE Moller, O Cohen, Y Yamaguchi, R Assiz, F Grigorescu, A Eberle, LA Morrow, AC Moses and JS Flier
Charles A. Dana Research Institute, Boston, MA.

Mutations of the insulin receptor gene are a cause of the type A syndrome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndrome including ovarian hyperandrogenism, moderate-to-severe degrees of insulin resistance, and acanthosis nigricans. We studied 22 unrelated women with insulin resistance (fasting insulin > 300 pM [50 microU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 microU/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proband with severe insulin resistance also were included in the study. Southern blotting experiments were performed to exclude gross gene deletions, insertions, or rearrangements. Exons 2-22 of the insulin receptor gene were polymerase chain reaction (PCR) amplified from genomic DNA and screened for nucleotide variation using single-strand conformation polymorphism (SSCP). No nucleotide variation between study subjects was detected in exons 4-6, 10-12, 15, 16, 18, 19, or 21. Sequencing of amplified DNA revealed that SSCP variants in exons 2, 3, 8, 9, and 17 corresponded to known silent polymorphisms within the coding region. Variants in exons 2, 9, 13, and 14 were caused by novel silent polymorphisms; variants in exons 7 and 22 were caused by nucleotide substitutions in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG-->CAG, Arg1174-->Gln) that involves the intracellular receptor beta-subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. McDonald, R. M Williams, F. M Regan, R. K Semple, and D. B Dunger IGF-I treatment of insulin resistance Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S51 - S56. [Abstract] [Full Text] [PDF]

				L. Jin, X.-M. Zhu, Q. Luo, Y. Qian, F. Jin, and H.-F. Huang A novel SNP at exon 17 of INSR is associated with decreased insulin sensitivity in Chinese women with PCOS Mol. Hum. Reprod., March 1, 2006; 12(3): 151 - 155. [Abstract] [Full Text] [PDF]

				J. Young, L. Morbois-Trabut, B. Couzinet, O. Lascols, E. Dion, V. Bereziat, B. Feve, I. Richard, J. Capeau, P. Chanson, et al. Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation Diabetes, June 1, 2005; 54(6): 1873 - 1878. [Abstract] [Full Text] [PDF]

				K. Hojlund, T. Hansen, M. Lajer, J. E. Henriksen, K. Levin, J. Lindholm, O. Pedersen, and H. Beck-Nielsen A Novel Syndrome of Autosomal-Dominant Hyperinsulinemic Hypoglycemia Linked to a Mutation in the Human Insulin Receptor Gene Diabetes, June 1, 2004; 53(6): 1592 - 1598. [Abstract] [Full Text] [PDF]

				R. Azziz, L. A. Sanchez, E. S. Knochenhauer, C. Moran, J. Lazenby, K. C. Stephens, K. Taylor, and L. R. Boots Androgen Excess in Women: Experience with Over 1000 Consecutive Patients J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 453 - 462. [Abstract] [Full Text] [PDF]

				The Rotterdam ESHRE/ASRM-sponsored PCOS consensus Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) Hum. Reprod., January 1, 2004; 19(1): 41 - 47. [Abstract] [Full Text] [PDF]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				N. A. Tritos and C. S. Mantzoros Syndromes of Severe Insulin Resistance J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3025 - 3030. [Full Text]

				A. Krook, J. P. Whitehead, S. P. Dobson, M. R. Griffiths, M. Ouwens, C. Baker, A. C. Hayward, S. K. Sen, J. A. Maassen, K. Siddle, et al. Two Naturally Occurring Insulin Receptor Tyrosine Kinase Domain Mutants Provide Evidence That Phosphoinositide 3-Kinase Activation Alone Is Not Sufficient for the Mediation of Insulin's Metabolic and Mitogenic Effects J. Biol. Chem., November 28, 1997; 272(48): 30208 - 30214. [Abstract] [Full Text] [PDF]

				C. Vigouroux, E. Khallouf, C. Bourut, J.-J. Robert, M. de Kerdanet, N. Tubiana-Rufi, S. Faure, J. Weissenbach, J. Capeau, and J. Magre Genetic Exclusion of 14 Candidate Genes in Lipoatropic Diabetes Using Linkage Analysis in 10 Consanguineous Families J. Clin. Endocrinol. Metab., October 1, 1997; 82(10): 3438 - 3444. [Abstract] [Full Text] [PDF]

				Y. Takahashi, K. Tobe, H. Kadowaki, D. Katsumata, Y. Fukushima, Y. Yazaki, Y. Akanuma, and T. Kadowaki Roles of Insulin Receptor Substrate-1 and Shc on Insulin-Like Growth Factor I Receptor Signaling in Early Passages of Cultured Human Fibroblasts Endocrinology, February 1, 1997; 138(2): 741 - 750. [Abstract] [Full Text] [PDF]

				A. Krook, D. E. Moller, K. Dib, and S. O'Rahilly Two Naturally Occurring Mutant Insulin Receptors Phosphorylate Insulin Receptor Substrate-1 (IRS-1) but Fail to Mediate the Biological Effects of Insulin J. Biol. Chem., March 22, 1996; 271(12): 7134 - 7140. [Abstract] [Full Text] [PDF]