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- Title
Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3.
- Authors
Farooqi, I Sadaf; Volders, Karolien; Stanhope, Richard; Heuschkel, Robert; White, Anne; Lank, Emma; Keogh, Julia; O'Rahilly, Stephen; Creemers, John W M
- Abstract
<bold>Context: </bold>Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported.<bold>Research Design and Methods: </bold>We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient.<bold>Results: </bold>In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome.<bold>Conclusion: </bold>This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.
- Subjects
AGE factors in disease; CELL culture; COMPARATIVE studies; GENETIC techniques; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; OBESITY; PROTEOLYTIC enzymes; RESEARCH; RESEARCH funding; EVALUATION research; HYPERPHAGIA; GENOTYPES
- Publication
Journal of Clinical Endocrinology & Metabolism, 2007, Vol 92, Issue 9, p3369
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2007-0687