Alternative splicing of exon 17 and a missense mutation in exon 20 of the insulin receptor gene in two brothers with a novel syndrome of insulin resistance (congenital fiber-type disproportion myopathy)

The insulin receptor (IR) in two brothers with a rare syndrome of congenita l muscle fiber type disproportion myopathy (CFTDM) associated with diabetes and severe insulin resistance was studied. By direct sequencing of Epstein -Barr virus-transformed lymphocytes both patients were found to be compound heterozygotes for mutations in the IR gene. The maternal allele was altern atively spliced in exon 17 due to a point mutation in the -1 donor splice s ite of the exon. The abnormal skipping of exon 17 shifts the am ino acid re ading frame and leads to a truncated IR, missing the entire tyrosine kinase domain. In the correct spliced variant, the point mutation is silent and r esults in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were presen t in the lymphocytes of the patients. Purified IR from 293 cells overexpres sing either of the two mutated receptors lacked basal or stimulated IR P-su bunit autophosphorylation. A third brother who inherited both normal allele s has an normal muscle phenotype and insulin sensitivity, suggesting a dire ct linkage of these IR mutations with the CFTDM phenotype. Copyright (C) 20 00 S. Karger AG, Basel.