Duckett, Katie [0000-0002-0222-1689], Williamson, Alice [0000-0002-7599-9301], Kincaid, John WR [0000-0003-0660-9813], Rainbow, Kara [0000-0002-8089-0693], Corbin, Laura J [0000-0002-4032-9500], Martin, Hilary C [0000-0002-4454-9084], Eberhardt, Ruth Y [0000-0001-6152-1369], Huang, Qin Qin [0000-0003-3073-717X], Hurles, Matthew E [0000-0002-2333-7015], Brauner, Raja [0000-0002-4456-4508], Delaney, Angela [0000-0002-0632-6365], Grinspon, Romina P [0000-0002-6291-1518], Hall, Janet E [0000-0003-4644-3061], Hirschhorn, Joel N [0000-0002-1650-7901], Palmert, Mark R [0000-0002-4096-0685], Lam, Brian YH [0000-0002-3638-9025], Timpson, Nicholas J [0000-0002-7141-9189], Clayton, Peter [0000-0003-1225-4537], Chan, Yee-Ming [0000-0003-0554-8502], Ong, Ken K [0000-0003-4689-7530], O'Rahilly, Stephen [0000-0003-2199-4449], Apollo - University of Cambridge Repository
المصدر:
Duckett, K, Williamson, A, Kincaid, J W R, Rainbow, K, Corbin, L J, Martin, H C, Eberhardt, R Y, Huang, Q Q, Hurles, M E, He, W, Brauner, R, Delaney, A, Dunkel, L, Grinspon, R P, Hall, J E, Hirschhorn, J N, Howard, S R, Latronico, A C, Jorge, A A L, Mcelreavey, K, Mericq, V, Merino, P M, Palmert, M R, Plummer, L, Rey, R A, Rezende, R C, Seminara, S B, Salnikov, K, Banerjee, I, Lam, B Y H, Perry, J R B, Timpson, N J, Clayton, P, Chan, Y-M, Ong, K K & O’rahilly, S 2023, ' Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty ', The Journal of Clinical Endocrinology & Metabolism . https://doi.org/10.1210/clinem/dgad373Test
ContextThe melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than non-carriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.ObjectiveTo determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).Design, Setting and ParticipantsWe examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterised the signalling properties of all non-synonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice breaking in the UK Biobank cohort.ResultsMC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 (2.2%), OR = 4.17, p = 0.001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 (0.6%), OR = 1.15, p = 0.779). In 246,328 women from UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (≥16 years) vs normal age at menarche (OR = 1.66, p = 3.90E-07).ConclusionsWe have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
