A NOVEL POINT MUTATION IN THE INSULIN GENE GIVING RISE TO HYPERPROINSULINEMIA

A 58-yr-old obese white Caucasian male type 2 diabetic, entered into t he UK Prospective Diabetes Study, was found to have raised fasting tot al proinsulin levels 708 pmol/L-1 (normal range, 3-16 pmol/L-1) and no rmal specific plasma insulin level 29 pmol/L-1 (normal range, 21-75 pm ol/L-1). Immunoreactive plasma insulin, measured by RIA, was 503 pmol/ L-1. DNA was extracted, the insulin gene amplified by the PCR, and by direct sequencing, a novel point mutation, G1552C, was identified, whi ch resulted in the substitution of proline (CCT) for arginine (CGT) at position 65. This prevented cleavage of the C-peptide A-chain dibasic cleavage site (lys-arg) by the processing protease in the pancreatic beta-cells. The plasma proinsulin and insulin levels were in accord wi th expression of both the wild-type and the mutant alleles. The G1552C mutation was not linked with diabetes, because it was present in a 37 -yr-old nondiabetic daughter and not in a 35-yr-old daughter who had h ad gestational diabetes.