Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome

The Journal of Clinical Investigation
Y TakahashiT Kadowaki

Abstract

Rabson-Mendenhall's syndrome is one of the most severe forms of insulin resistance syndrome. We analyzed an English patient described elsewhere and found novel mutations in both alleles of the insulin receptor gene. One is a substitution of G for A at the 3' splice acceptor site of intron 4, and the other is an eight-base pair deletion in exon 12. Both decrease mRNA expression in a cis-dominant manner, and are predicted to produce severely truncated proteins. Surprisingly, nearly normal insulin receptor levels were expressed in the patient's lymphocytes, although the level of expression assessed by immunoblot was approximately 10% of the control cells. Insulin binding affinity was markedly reduced, but insulin-dependent tyrosine kinase activity was present. Analyzing the insulin receptor mRNA of the patient's lymphocytes by reverse transcription PCR, we discovered aberrant splicing caused by activation of a cryptic splice site in exon 5, resulting in a four-amino acid deletion and one amino acid substitution, but restoring an open reading frame. Skipped exon 5, another aberrant splicing, was found in both the patient and the mother who had the heterozygotic mutation, whereas activation of the cryptic splice site occurred almost...Continue Reading

References

Feb 1, 1992·Clinical Endocrinology·S O'Rahilly, D E Moller
Sep 26, 1991·The New England Journal of Medicine·D E Moller, J S Flier
Apr 1, 1990·The Journal of Clinical Endocrinology and Metabolism·R YamamotoY Akanuma
Nov 15, 1990·The New England Journal of Medicine·J D QuinA C MacCuish
Aug 28, 1997·Biochemical and Biophysical Research Communications·H KadowakiT Kadowaki

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Citations

Apr 1, 1995·Diabetes/metabolism Reviews·D Accili
Jun 6, 2002·Pediatric Dermatology·Christina A Hardaway, Neil F Gibbs
Sep 6, 2005·Nucleic Acids Research·Jana KrálovicováIgor Vorechovský
Dec 1, 1992·Journal of Endocrinological Investigation·D AcciliS I Taylor
Oct 7, 2008·Clinica Chimica Acta; International Journal of Clinical Chemistry·Chandrakesan ParthasarathyKarundevi Balasubramanian
Dec 12, 2001·Endocrine Reviews·J NakaeD Accili

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