ESPEYB21 7. Puberty Clinical Guidance and Studies (8 abstracts)
7.8. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty
Duckett K , Williamson A , Kincaid JWR , Rainbow K , Corbin LJ , Martin HC , Eberhardt RY , Huang QQ , Hurles ME , He W , Brauner R , Delaney A , Dunkel L , Grinspon RP , Hall JE , Hirschhorn JN , Howard SR , Latronico AC , Jorge AAL , McElreavey K , Mericq V , Merino PM , Palmert MR , Plummer L , Rey RA , Rezende RC , Seminara SB , Salnikov K , Banerjee I , Lam BYH , Perry JRB , Timpson NJ , Clayton P , Chan YM , Ong KK & O’Rahilly S
J Clin Endocrinol Metab. 2023;108(12):e1580-e1587. doi: 0.1210/clinem/dgad373. PMID: 37339320. https://academic.oup.com/jcem/article/108/12/e1580/7204094?login=true
Brief Summary: this large patient cohort study identified an overrepresentation of functionally damaging variants in MC3R in individuals with constitutional delay of growth and puberty but not in patients with IHH.
Melanocortin 3 receptor (MC3R) is a permissive signal expressed by hypothalamic kisspeptin-neurokinin B-dynorphin (KNDY) neurons. It activates puberty through the leptin-proopiomelanocortin pathway in response to nutritional signaling1. Variants in MC3R have been associated with later age at puberty and a severely disruptive variant has been recently reported to be associated with extreme pubertal delay1. The authors hypothesized that deleterious variants of MC3R could also be associated with constitutional delay of growth and puberty (CDGP).
MC3R was sequenced in 362 adolescents with CDGP and 657 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Variant frequencies in those groups were compared to 5774 controls from a population-based cohort. Loss-of-function variants were infrequent but overrepresented in patients with CDGP compared to controls (OR =4.17; P =.001). There was no evidence of overrepresentation in patients with nIHH (OR =1.15; P =.779). In 246,328 women from the UK Biobank study, predicted deleterious variants were more frequently found in those self-reporting delayed vs normal age at menarche (OR =1.66; P =3.90E-07).
These results indicate that MC3R is a permissive rather than essential factor which influences pubertal timing within a wider polygenic and environmental context.
Reference: 1. Lam BYH, Williamson A, Finer S, Day FR, Tadross JA, Gonçalves Soares A, Wade K, Sweeney P, Bedenbaugh MN, Porter DT, Melvin A, Ellacott KLJ, Lippert RN, Buller S, Rosmaninho-Salgado J, Dowsett GKC, Ridley KE, Xu Z, Cimino I, Rimmington D, Rainbow K, Duckett K, Holmqvist S, Khan A, Dai X, Bochukova EG; Genes & Health Research Team; Trembath RC, Martin HC, Coll AP, Rowitch DH, Wareham NJ, van Heel DA, Timpson N, Simerly RB, Ong KK, Cone RD, Langenberg C, Perry JRB, Yeo GS, O’Rahilly S. MC3R links nutritional state to childhood growth and the timing of puberty. Nature 2021;599(7885):436-441.
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ESPE Yearbook of Paediatric Endocrinology
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