A 3-BASEPAIR IN-FRAME DELETION (DELTA-LEU(999)) IN EXON-17 OF THE INSULIN-RECEPTOR GENE IN A FAMILY WITH INSULIN-RESISTANCE

We studied a woman with acanthosis nigricans and insulin resistance. T he patient's Epstein-Barr virus-transformed lymphocytes revealed sligh tly decreased insulin binding and markedly decreased insulin-stimulate d autophosphorylation of the insulin receptor. The nucleotide sequence analysis of the patient's genomic DNA revealed a 3-basepair in-frame deletion in one allele, resulting in the loss of leucine at position 9 99 of the insulin receptor (Delta Leu(999)). The messenger ribonucleic acid transcripts from the mutant allele in the patient's lymphocytes were not decreased. Insulin-stimulated autophosphorylation of the insu lin receptor from cells expressing Delta Leu(999) mutant insulin recep tor complementary DNA was markedly decreased. The proband, her mother, elder brother, and younger brother, who were heterozygous for this mu tation, showed moderate or marked hyperinsulinemia during oral glucose tolerance tests. Although fasting glucose levels were normal and fast ing insulin values were preserved in all subjects with the mutation fo r the 8-yr period of observation, a tendency of progressive increase i n postload glucose levels was observed. These results suggest that the Delta Leu(999) mutation, which reduces tyrosine kinase activity, was responsible for insulin resistance and contributed to postload hypergl ycemia.