Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3. PC2 is a type II proinsulin-processing enzyme, and it cleaves the proinsulin molecule on the COOH-terminal side of dibasic peptide, Lys64-Arg65, which joins the C-peptide and the A-chain domains. We have previously cloned and characterized the exon-intron organization of the human PC2 gene (gene symbol PCSK2), localized this gene to human chromosome 20 band p11.2 by fluorescence in situ hybridization, and identified a simple tandem-repeat DNA polymorphism (STRP) in intron 2 of the form (CA)n, suitable for genetic studies. Since non-insulin-dependent diabetes mellitus (NIDDM) is associated with increased secretion of proinsulin and proinsulin-like molecules, we conducted a case-control study to determine whether a genetic variation in PCSK2 might contribute to the development of NIDDM. The study population consisted of 152 Japanese NIDDM subjects and 102 normal healthy nondiabetic control subjects matched for age and body mass index. The subjects were genotyped at the STRP in intron 2, and the results indicated a significant difference (P = 0.004) in the overall allele frequency distribution between the two groups. The A1 allele was found more frequently in NIDDM than in nondiabetic subjects (11 vs. 4%, P = 0.0068). The NIDDM patients were divided into two subgroups according to the presence or absence of the A1 allele. There were no significant differences between these two subgroups with respect to age, sex, body mass index, family history of NIDDM, or current HbAlc, fasting plasma glucose, and serum proinsulin levels. The 12 exons of the PC2 gene of 60 NIDDM subjects were screened for mutations that might explain the observed association using the technique of single-strand conformational polymorphism analysis. A single variant was noted in exon 1. One NEDDM subject was heterozygous for a G→T substitution at 2 base pairs before the translational start site. This nucleotide substitution creates an in-frame methionine codon, which, if functional, would generate a protein with two methionine residues at its NH2-terminus rather than one. The functional consequences of such a change on the enzymatic properties of PC2 are unknown.

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