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)

TY - JOUR

T1 - 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)

AU - Vorwerk, P

AU - Christoffersen, C T

AU - Müller, J

AU - Vestergaard, H

AU - Pedersen, O

AU - De Meyts, P

AU - Vestergaard, Henrik

N1 - Copyright 2000 S. Karger AG, Basel

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

KW - Adolescent

KW - Alleles

KW - Alternative Splicing

KW - Base Sequence

KW - Child

KW - DNA Primers

KW - DNA, Complementary

KW - Exons

KW - Female

KW - Heterozygote

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Male

KW - Mutagenesis, Site-Directed

KW - Mutation, Missense

KW - Myopathies, Structural, Congenital

KW - Pedigree

KW - Phenotype

KW - Point Mutation

KW - Polymorphism, Genetic

KW - Protein Structure, Tertiary

KW - Protein-Tyrosine Kinases

KW - Receptor, Insulin

KW - Syndrome

U2 - 10.1159/000023464

DO - 10.1159/000023464

M3 - Journal article

C2 - 10844410

SN - 0301-0163

VL - 52

SP - 211

EP - 220

JO - Hormone Research

JF - Hormone Research

IS - 5

ER -