Severe resistance to insulin and insulin-like growth factor-I in cells from a patient with leprechaunism as a result of two mutations in the tyrosine kinase domain of the insulin receptor

Metabolism: Clinical and Experimental
C Desbois-MouthonM Caron

Abstract

We studied the biological properties of insulin receptors (IRs) and insulin-like growth factor-I (IGF-I) receptors in cultured fibroblasts from a patient with leprechaunism (leprechaun Par-1). Patient cells displayed normal insulin binding capacity and affinity. Basal in vivo autophosphorylation and in vitro exogenous kinase activity of patient IRs were elevated twofold to threefold compared with control receptors, and insulin had no further effect on these processes. Moreover, patient IRs were unable to promote the stimulation of metabolic and mitogenic pathways. IR substrate-1 (IRS-1) and mitogen-activated protein (MAP) kinase tyrosine phosphorylation and glycogen and DNA synthesis were not increased in the basal state in patient fibroblasts and were also insensitive to the stimulatory effect of insulin. As for IGF-I, although binding and receptor kinase activity were normal, the ability to stimulate glycogen and DNA synthesis was altered in patient cells. Two mutant alleles of the IR gene were detected by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. The maternal allele contained a point mutation in exon 18 encoding the tryptophan-for-arginine substitution at position 1092, and the paternal allele had...Continue Reading

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Jul 19, 2013·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Hongyan LingLiang Zhang
Oct 30, 1998·Endocrine Reviews·S JainM E Geffner
May 28, 2005·Diabetes·Jacques YoungCorinne Vigouroux
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Feb 1, 2008·Clinical & Experimental Metastasis·Sharon BarrJohn D Haley
Apr 22, 2011·Archives of Physiology and Biochemistry·Manuel Benito

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