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Hyperphagia and Early-Onset Obesity due to a Novel Homozygous Missense Mutation in Prohormone Convertase 1/3

University Department of Clinical Biochemistry (I.S.F., E.L., J.K., S.O.), Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom; Department for Human Genetics (K.V., J.W.M.C.), University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium; Department of Endocrinology (R.S.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Paediatric Gastroenterology (R.H.), Royal Free Hospital, London NW3 5NU, United Kingdom; and Endocrine Sciences (A.W.), Faculty of Life Sciences and Medical and Human Sciences, University of Manchester, Manchester M13 9PT, United Kingdom

Address all correspondence and requests for reprints to: Stephen O’Rahilly, University Department of Clinical Biochemistry, Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom. E-mail: so104{at}medschl.cam.ac.uk.

Context: 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.

Research Design and Methods: 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.

Results: 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.

Conclusion: This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.

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