TY - JOUR
T1 - Obesity and Hyperphagia With Increased Defective ACTH
T2 - A Novel POMC Variant
AU - van der Valk, Eline S.
AU - Kleinendorst, Lotte
AU - Delhanty, Patric J.D.
AU - van der Voorn, Bibian
AU - Visser, Jenny A.
AU - van Haelst, M. M.
AU - de Graaff, Laura C.G.
AU - Huisman, Martin
AU - White, Anne
AU - Ito, Shosuke
AU - Wakamatsu, Kazumasa
AU - de Rijke, Yolanda B.
AU - van den Akker, Erica L.T.
AU - Iyer, Anand M.
AU - van Rossum, Elisabeth F.C.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
PY - 2022/9/1
Y1 - 2022/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85136910394&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgac342
DO - 10.1210/clinem/dgac342
M3 - Article
C2 - 35737586
AN - SCOPUS:85136910394
SN - 0021-972X
VL - 107
SP - e3699-e3704
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 9
ER -