Hyperphagia and Early-Onset Obesity due to a Novel Homozygous Missense Mutation in Prohormone Convertase 1/3
Abstract
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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The Ser307Leu mutation is within the catalytic domain and severely impairs the catalytic activity of the enzyme.
“This mutation is also within the catalytic domain and severely impairs the catalytic activity of the enzyme.68”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [68]
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- Authors
- Farooqi, I. S., Volders, K., Stanhope, R., Heuschkel, R., White, A., Lank, E., Keogh, J., O’Rahilly, S., & Creemers, J. W. M.
- Affiliations
- University of Cambridge (GB)
- KU Leuven (BE)
- Great Ormond Street Hospital (GB)
- The Royal Free Hospital (GB)
- University of Manchester (GB)
- Corresponding author
- Farooqi, I. Sadaf
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2007-09-01
- Volume
- 92
- Issue
- 9
- Pages
- 3369-3373
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2160679927
- Cited by
- 218
- References
- 31
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 14 · 2022: 11 · 2021: 11 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 13 · 2015: 15 · 2014: 15 · 2013: 17 · 2012: 17
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- Wellcome Trust (068086)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- prohormone convertase 1/3, hyperphagia, early-onset obesity, missense mutations, consanguinity, diarrhea, enzyme activity, dietary intake, childhood obesity
- MeSH terms
- Cells, Cultured, Child, Homozygote, Humans, Hyperphagia, Male, Obesity, Transfection, Age of Onset, Mutation, Missense, Proprotein Convertase 1
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