Nature Genetics
10, 135 - 142 (1995)
doi:10.1038/ng0695-135
Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activityJürgen K. Naggert1, Lloyd D. Fricker2, Oleg Varlamov2, Patsy M. Nishina1, Yves Rouille3, Donald F. Steiner3, Raymond J. Carroll3, Beverly J. Paigen1
& Edward H. Leiter1
1The Jackson Laboratory, Bar Harbor, Maine 04609, USA
2Deptartment of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
3Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA Correspondence should be addressed to J.K.N. Mice homozygous for the fat mutation develop obesity and hyperglycaemia that can be suppressed by treatment with exogenous insulin. The fat mutation maps to mouse chromosome 8, very close to the gene for carboxypeptidase E (Cpe), which encodes an enzyme (CPE) that processes prohormone intermediates such as proinsulfn. We now demonstrate a defect in proinsulin processing associated with the virtual absence of CPE activity in extracts of fat/fat pancreatic islets and pituitaries. A single Ser202Pro mutation distinguishes the mutant Cpe allele, and abolishes enzymatic activity in vitro. Thus, the fat mutation represents the first demonstration of an obesity−diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.
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