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- Title
Obesity and Hyperphagia With Increased Defective ACTH: A Novel POMC Variant.
- Authors
van der Valk, Eline S.; Kleinendorst, Lotte; Delhanty, Patric J. D.; van der Voorn, Bibian; Visser, Jenny A.; van Haelst, M. M.; de Graaff, Laura C. G.; Huisman, Martin; White, Anne; Shosuke Ito; Kazumasa Wakamatsu; de Rijke, Yolanda B.; van den Akker, Erica L. T.; Iyer, Anand M.; van Rossum, Elisabeth F. C.
- Abstract
Objective: Patients with pro-opiomelanocortin (POMC) defects generally present with early-onset obesity, hyperphagia, hypopigmentation and adrenocorticotropin (ACTH) deficiency. Rodent models suggest that adequate cleavage of ACTH to α-melanocortin–stimulating hormone (α-MSH) and desacetyl-α-melanocortin–stimulating hormone (d-α-MSH) by prohormone convertase 2 at the KKRR region is required for regulating food intake and energy balance. Methods: We present 2 sisters with a novel POMC gene variant, leading to an ACTH defect at the prohormone convertase 2 cleavage site, and performed functional studies of this variant. Results: The patients had obesity, hyperphagia and hypocortisolism, with markerly raised levels of ACTH but unaffected pigmentation. Their ACTH has reduced potency to stimulate the melanocortin (MC) 2 receptor, explaining their hypocortisolism. Conclusion: The hyperphagia and obesity support evidence that adequate cleavage of ACTH to α-MSH and d-α-MSH is also required in humans for feeding control.
- Subjects
HYPOPIGMENTATION; ADRENOCORTICOTROPIC hormone; MELANOCORTIN receptors
- Publication
Journal of Clinical Endocrinology & Metabolism, 2022, Vol 107, Issue 9, pe3699
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/clinem/dgac342