Mutations in the insulin gene can impair the bioactivity of the insulin molecule. Previously, two classes of mutations have been identified: 1) those that impair posttranslational processing of proinsulin to insulin, and 2) those that alter the structure of the insulin molecule, thereby reducing the affinity of the molecule for the insulin receptor. We have investigated two apparently unrelated patients, both of which have mutations that inhibit the conversion of proinsulin to insulin. By directly sequencing genomic DNA amplified by polymerase chain reaction, we have demonstrated that both patients are heterozygous for the same point mutation converting codon 65 from an arginine (CGT) to a histidine (CAT) codon. Because Arg65 is one of the two dibasic amino acids at the site of proteolytic cleavage between the insulin A-chain and C-peptide, this mutation explains the impairment in the cleavage of proinsulin to insulin. Interestingly, the same His65 mutation has been identified in the insulin gene of a Japanese kindred with familial hyperproinsulinemia. Thus, this mutation has occurred in three apparently unrelated kindreds from two different racial groups. This observation is consistent with the hypothesis that the dinucleotide sequence CpG, the first two nucleotides in the arginine (CGT) codon, is a "hot spot" for mutations.
|Number of pages||6|
|Journal||Journal of Clinical Endocrinology and Metabolism|
|Publication status||Published - Jul 1990|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism