Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature
Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature
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DOI：
10.1111/j.1365-2265.2010.03911.x
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发表时间：
2011-02-01
影响因子：
3.2
通讯作者：
Fujieda, Kenji
中科院分区：
文献类型：
--
作者：
Inoue, Hiroshi;Kangawa, Natsumi;Fujieda, Kenji
背景生长激素释放激素受体(GHRHR)基因突变在不同种族的孤立性生长激素缺乏症(IGHD)IB型患者中被发现。本研究旨在探讨GHRHR基因突变在日本人矮小发病机制中的作用。设计对127例日本IGHD(n=14)或特发性矮小(ISS；n=113)患者进行GHRHR基因测序。结果在一个IGHD家系中发现了一个新的纯合子E382E(c.1146G>；A)同义突变，位于外显子12的最后一个碱基。体外剪接研究表明，该突变导致了外显子12的跳跃。在一例ISS患者中，在GHRHR启动子远端Pit-1 P2结合元件中发现了ATG-166T和GT；C杂合突变。在两名对照受试者中，检测到了一个相近但截然不同的变异ATG-164T>；C。功能研究表明，这两个启动子变异体通过改变Pit-1的结合能力来降低启动子的活性。在患者和对照组中也都发现了4个错义突变，但没有检测到功能后果。结论GHRHR纯合突变是罕见的，只在一个日本IGHD家系中检测到。需要进一步的研究来阐明杂合功能启动子变异对生长激素缺乏症、ISS和正常身高变异的遗传贡献。
P>ContextGrowth hormone-releasing hormone receptor (GHRHR) gene mutations have been identified in patients of different ethnic origins with isolated GH deficiency (IGHD) type IB. However, the prevalence of these mutations in the Japanese population has yet to be fully determined.ObjectivesThis study aimed to evaluate the contributions of GHRHR mutations to the molecular mechanism underlying short stature in Japanese subjects.DesignThe GHRHR gene was sequenced in 127 unrelated Japanese patients with either IGHD (n = 14) or idiopathic short stature (ISS; n = 113). Sequence variants were evaluated in family members and 188 controls, and then examined in functional studies.ResultsA novel homozygous E382E (c.1146G > A) synonymous variant, at the last base of exon 12, was identified in an IGHD family with two affected sisters. In vitro splicing studies showed this mutation to result in skipping of exon 12. In one ISS patient, a heterozygous ATG-166T > C variant was found in the distal Pit-1 P2 binding element of the GHRHR promoter. In two control subjects, a close but distinct variant, ATG-164T > C, was detected. Functional studies showed that both promoter variants diminish promoter activity by altering Pit-1 binding ability. Four missense variants were also found in both patient and control groups but had no detectable functional consequences.ConclusionsThe homozygous GHRHR mutation was rare, being detected in only one Japanese IGHD family. Future research is needed to clarify the genetic contributions of heterozygous functional promoter variants to GHD, ISS and normal-stature variations.