Identification and Functional Analysis of Novel Human Growth Hormone Secretagogue Receptor (GHSR) Gene Mutations in Japanese Subjects with Short Stature
Identification and Functional Analysis of Novel Human Growth Hormone Secretagogue Receptor (GHSR) Gene Mutations in Japanese Subjects with Short Stature
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DOI：
10.1210/jc.2010-1570
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发表时间：
2011-02-01
影响因子：
5.8
通讯作者：
Fujieda, Kenji
中科院分区：
文献类型：
--
作者：
Inoue, Hiroshi;Kangawa, Natsumi;Fujieda, Kenji
背景：身材矮小（SS）是一种多因素的发育状况，具有重要的遗传成分。最近的研究表明，GH促分泌素受体1A（GHSR 1A）基因的罕见突变可能是导致家族性SS或GH缺乏症的原因之一。目的：本研究的目的是评估GHSR 1A突变对日本受试者SS潜在分子机制的贡献。我们在127例诊断为单纯GH缺乏症或特发性SS的无关日本SS患者中进行了GHSR 1A基因突变筛查。在188名对照者中分析了鉴定的突变，并在异源表达系统中检查了它们的功能特性。结果：鉴定出四种新的杂合GHSR 1A突变（Delta Q36，P108 L，C173 R和D246 A）。表达研究表明，这些突变具有不同的功能后果：1）所有突变均对GHSR 1A的组成性信号传导活性表现出功能丧失效应，但丧失程度差异很大：2）C173 R导致突变蛋白的胞内滞留，导致受体功能完全丧失; 3）P108 L导致与ghrelin的结合亲和力大幅降低，但不影响其表面表达：4）D246 A独特地损害激动剂和反向激动剂刺激的受体信号传导;和5）Δ Q36仅显示组成型活性的细微降低。这些推定的功能突变的累积频率显着高于患者组比对照组（4.72比0.53%; P = 0.019;比值比= 9.28; 95%置信区间，1.10-78.0）。结论：我们的研究结果表明，GHSR 1A突变有助于遗传病因的SS在日本人口。（临床内分泌代谢杂志96：E373-E378，2011）
Context: Short stature (SS) is a multifactorial developmental condition with a significant genetic component. Recent studies have revealed that rare deleterious mutations in the GH-secretagogue receptor type 1A (GHSR1A) gene could be a cause of familial SS or GH deficiency.Objective: The aim of this study was to evaluate the contribution of GHSR1A mutations to the molecular mechanism underlying SS in Japanese subjects.Methods: We performed mutational screening of the GHSR1A gene in 127 unrelated Japanese SS patients diagnosed with either isolated GH deficiency or idiopathic SS. Identified mutations were analyzed in 188 control subjects, and their functional properties were examined in a heterologous expression system.Results: Four novel heterozygous GHSR1A mutations were identified (Delta Q36, P108L, C173R, and D246A). Expression studies demonstrated that these mutations had varying functional consequences: 1) all mutations showed a loss-of-function effect on the constitutive signaling activity of GHSR1A, but the degree of loss varied widely; 2) C173R caused intracellular retention of the mutated protein, resulting in total loss of receptor function; 3) P108L resulted in a large decrease in binding affinity to ghrelin, without affecting its surface expression; 4) D246A uniquely impaired agonist-and inverse agonist-stimulated receptor signaling; and 5) Delta Q36 showed only a subtle reduction in constitutive activity. The cumulative frequency of these putative functional mutations was significantly higher in the patient group than in controls (4.72 vs. 0.53%; P = 0.019; odds ratio = 9.28; 95% confidence interval, 1.10-78.0).Conclusions: Our results suggest that GHSR1A mutations contribute to the genetic etiology of SS in the Japanese population. (J Clin Endocrinol Metab 96: E373-E378, 2011)