title: 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).
abstract: The insulin receptor (IR) in two brothers with a rare syndrome of congenital 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 alternatively spliced in exon 17 due to a point mutation in the -1 donor splice site of the exon. The abnormal skipping of exon 17 shifts the amino acid reading frame and leads to a truncated IR, missing the entire tyrosine kinase domain. In the correct spliced variant, the point mutation is silent and results in a normally translated IR. The paternal allele carries a missense mutation in the tyrosine kinase domain. All three cDNA variants were present in the lymphocytes of the patients. Purified IR from 293 cells overexpressing either of the two mutated receptors lacked basal or stimulated IR beta-subunit autophosphorylation. A third brother who inherited both normal alleles has an normal muscle phenotype and insulin sensitivity, suggesting a direct linkage of these IR mutations with the CFTDM phenotype.
authors.affiliation: Department of Pediatric Hematology and Oncology, Otto von Guericke University, Magdeburg, Germany. Peter.Vorwerk@medizin.uni-magdeburg.de
authors.forename: P
authors.initials: P
authors.lastname: Vorwerk
authors.forename: C T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: J
authors.initials: J
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: Vestergaard
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: P
authors.initials: P
authors.lastname: De Meyts
mesh_terms: D000293:Adolescent; D000483:Alleles; D017398:Alternative Splicing; D001483:Base Sequence; D002648:Child; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin