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)
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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). / Vorwerk, P; Christoffersen, C T; Müller, J; Vestergaard, H; Pedersen, O; De Meyts, P; Vestergaard, Henrik.
I: Hormone Research, Bind 52, Nr. 5, 1999, s. 211-20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 52
SP - 211
EP - 220
JO - Hormone Research
JF - Hormone Research
SN - 0301-0163
IS - 5
ER -
ID: 92192326