S. Ohagi et al., HUMAN PROHORMONE CONVERTASE-3 GENE - EXON-INTRON ORGANIZATION AND MOLECULAR SCANNING FOR MUTATIONS IN JAPANESE SUBJECTS WITH NIDDM, Diabetes, 45(7), 1996, pp. 897-901
Citations number
32
Categorie Soggetti
Endocrynology & Metabolism","Medicine, General & Internal
Proinsulin is converted to insulin by the concerted action of two sequ
ence-specific subtilisin-like proteases termed prohormone convertase 2
(PC2) and prohormone convertase 3 (PC3), PC3 is a type I proinsulin-p
rocessing enzyme that initiates the sequential processing of proinsuli
n to insulin by cleaving the proinsulin molecule on the COOH-terminal
side of the dibasic peptide, Arg(31)-Arg(32), joining the B-chain and
C-peptide, Thus, PC3 plays a key role in regulating insulin biosynthes
is, Expressions of insulin and PC3, but not PC2, are coordinately regu
lated by glucose, consistent with the important role of PC3 in regulat
ing proinsulin processing, NIDDM is associated with increased secretio
n of proinsulin and proinsulin-like molecules, suggesting that mutatio
ns in the PC3 gene may be involved in the development of this disorder
, To examine this hypothesis, we have isolated and characterized the h
uman PC3 gene and screened it for mutations in a group of Japanese sub
jects with NIDDM, The PC3 gene consists of 14 exons spanning more than
35 kb, The exon-intron organization of PC2 and PC3 genes are conserve
d, consistent with a common evolutionary origin for the prohormone con
vertase gene family, Single-strand conformational analysis and nucleot
ide sequencing of the entire coding region of the PC3 gene in 102 Japa
nese subjects with NIDDM revealed missense mutations in exons 2 (Arg/G
ln(53)) and 14 (Gln/Glu(638)), neither of which was associated with NI
DDM in this population, These data suggest that genetic variation in t
he PC3 gene is unlikely to be a major contributor to NIDDM susceptibil
ity in Japanese.