A novel mutation of insulin receptor gene (INSR gene) was identified in a three generation family with phenotypical variety. Proband was a 12-year-old Japanese girl with type A insulin resistance. She showed diabetes mellitus with severe acanthosis nigricans and hyperinsulinemia without obesity. Using direct sequencing, a heterozygous nonsense mutation causing premature termination at amino acid 331 in the α subunit of INSR gene (R331X) was identified. Her father, 40 years old, was not obese but showed impaired glucose tolerance. Her paternal grandmother, 66 years old, has been suffered from diabetes mellitus for 15 years. Interestingly, they had the same mutation. One case of leprechaunism bearing homozygous mutation at codon 331 was identified. These findings led to the hypothesis that R331X may contribute to the variation of DM in the general population in Japan. An extensive search was done in 272 participants in a group medical examination that included 92 healthy cases of normoglycemia and 180 cases already diagnosed type 2 DM or detected hyperglycemia. The search, however, failed to detect any R331X mutation in this local population. In addition, the proband showed low level C-peptide/insulin molar ratio, indicating that this ratio is considered to be a useful index for identifying patients with genetic insulin resistance. In conclusion, a nonsense mutation causing premature termination after amino acid 331 in the α subunit of the insulin receptor was identified in Japanese diabetes patients. Further investigations are called for to address the molecular mechanism.
The Japan Endocrine Society