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 pre sent. A 75-g oral glucose tolerance test showed a diabetic pattern, an d fasting insulinemia was 780 pmol/L. Insulin binding was normal, but autophosphorylation and tyrosine kinase activity were reduced in parti ally purified insulin receptors from Epstein-Barr virus-transformed ly mphocytes. The nucleotide sequence for all 22 exons of the insulin rec eptor gene was determined by direct sequencing of genomic DNA amplifie d with the polymerase chain reaction. Substitution of valine for glyci ne at codon 1008 in the tyrosine kinase domain was identified in one a llele. 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 hyperi nsulinemia, but the mother and two brothers had normal glucose toleran ce. We conclude that a single mutant allele in the tyrosine kinase dom ain caused the insulin resistance.