Jk. Naggert et al., HYPERPROINSULINAEMIA IN OBESE FAT FAT MICE ASSOCIATED WITH A CARBOXYPEPTIDASE-E MUTATION WHICH REDUCES ENZYME-ACTIVITY/, Nature genetics, 10(2), 1995, pp. 135-142
Mice homozygous for the fat mutation develop obesity and hyperglycaemi
a that can be suppressed by treatment with exogenous insulin. The fat
mutation maps to mouse chromosome 8, very close to the gene for carbox
ypeptidase E (Cpe), which encodes an enzyme (CPE) that processes proho
rmone intermediates such as proinsulin. We now demonstrate a defect in
proinsulin processing associated with the virtual absence of CPE acti
vity in extracts of fat/fat pancreatic islets and pituitaries. A singl
e Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishe
s enzymatic activity in vitro. Thus, the fat mutation represents the f
irst demonstration of an obesity-diabetes syndrome elicited by a genet
ic defect in a prohormone processing pathway.