Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.
Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.
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DOI：
10.1210/clinem/dgad373
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发表时间：
2023-11-17
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影响因子：
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黑素皮质素3受体(MC3R)最近被认为是青春期时机、线性生长和人类和小鼠瘦体重获得的关键调节因子。在基于人群的研究中，MC3R有害变异的杂合子携带者报告的青春期开始时间比非携带者更晚。然而，这种变异在青春期发育临床障碍患者中的频率目前尚不清楚。这项工作旨在确定有害的MC3R变异体是否更多地出现在临床表现为生长和青春期体质延迟(CDGP)或正常的特发性低促性腺激素减退(NIHH)的患者中。我们检测了362名临床诊断为CDGP的青少年和657名nIHH患者的MC3R序列，实验表征了所有发现的非同义变体的信号特性，并将它们的频率与5774名来自人群队列的对照进行了比较。此外，在英国生物库队列中，我们建立了自我报告的月经初潮延迟和正常时间的月经初潮/嗓音中断的个体中预测的有害变异的相对频率。MC3R功能缺失变异很少见，但在CDGP患者中过度表达(8/362[2.2%]；OR=4.17；P=.001)。在nIHH患者中没有强烈的证据表明过度表达(4/657[0.6%]；OR=1.15；P=.779)。在来自英国生物库的246328名女性中，那些自我报告的初潮年龄延迟(年龄≥16岁)的女性比正常初潮年龄的女性更容易发现预测的有害变异(OR=1.66；P=3.90E-07)。我们发现有证据表明，MC3R的功能破坏性变异在CDGP患者中过度表达，但不是这种表型的常见原因。
The 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 noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. This work aimed to 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). We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous 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. MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
5.8
作者：
Cassatella D;Howard SR;Acierno JS;Xu C;Papadakis GE;Santoni FA;Dwyer AA;Santini S;Sykiotis GP;Chambion C;Meylan J;Marino L;Favre L;Li J;Liu X;Zhang J;Bouloux PM;Geyter C;Paepe A;Dhillo WS;Ferrara JM;Hauschild M;Lang-Muritano M;Lemke JR;Flück C;Nemeth A;Phan-Hug F;Pignatelli D;Popovic V;Pekic S;Quinton R;Szinnai G;l'Allemand D;Konrad D;Sharif S;Iyidir ÖT;Stevenson BJ;Yang H;Dunkel L;Pitteloud N
通讯作者：
Pitteloud N
影响因子：
8.1
作者：
Lam BYH;Cimino I;Polex-Wolf J;Nicole Kohnke S;Rimmington D;Iyemere V;Heeley N;Cossetti C;Schulte R;Saraiva LR;Logan DW;Blouet C;O'Rahilly S;Coll AP;Yeo GSH
通讯作者：
Yeo GSH
影响因子：
5.8
作者：
Jonsdottir-Lewis, Elfa;Feld, Amalia;Chan, Yee-Ming
通讯作者：
Chan, Yee-Ming
影响因子：
--
作者：
Northstone, Kate;Lewcock, Melanie;Wells, Nicholas
通讯作者：
Wells, Nicholas