A glycine-1008 to valine mutation in the insulin receptor in a woman with type A insulin resistance.

We examined the insulin receptor gene in a Japanese woman with type A insulin resistance. Acanthosis nigricans and polycystic ovary were present. A 75-g oral glucose tolerance test showed a diabetic pattern, and fasting insulinemia was 780 pmol/L. Insulin binding was normal, but autophosphorylation and tyrosine kinase activity were reduced in partially purified insulin receptors from Epstein-Barr virus-transformed lymphocytes. The nucleotide sequence for all 22 exons of the insulin receptor gene was determined by direct sequencing of genomic DNA amplified with the polymerase chain reaction. Substitution of valine for glycine at codon 1008 in the tyrosine kinase domain was identified in one allele. This was the same mutation found in another patient, but there was no relationship between the two families. The father had the same mutation in one allele and impaired glucose tolerance with mild hyperinsulinemia, but the mother and two brothers had normal glucose tolerance. We conclude that a single mutant allele in the tyrosine kinase domain caused the insulin resistance.