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 (PC3). PC3 is a type I
proinsulin-processing
enzyme that initiates the sequential processing of
proinsulin to
insulin by cleaving the
proinsulin molecule on the COOH-terminal side of the dibasic
peptide, Arg31-Arg32, joining the B-chain and
C-peptide. Thus, PC3 plays a key role in regulating
insulin biosynthesis. Expressions of
insulin and PC3, but not PC2, are coordinately regulated by
glucose, consistent with the important role of PC3 in regulating
proinsulin processing.
NIDDM is associated with increased secretion of
proinsulin and
proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with
NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the
prohormone convertase gene family. Single-strand conformational analysis and
nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with
NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with
NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to
NIDDM susceptibility in Japanese.