Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure
Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure
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SOHLH2 基因的新变异与人类卵巢早衰有关
DOI：
10.1016/j.fertnstert.2014.01.001
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发表时间：
2014-04-01
影响因子：
6.7
通讯作者：
Chen, Zi-Jiang
中科院分区：
文献类型：
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作者：
Qin, Yingying;Jiao, Xue;Chen, Zi-Jiang
目的：探讨SOHLH2基因变异是否与不同种族的人卵巢早衰（POF）有关。设计：病例-对照遗传研究。地点：大学医院。患者：中国（364例）和塞尔维亚（197例）女性非综合征性POF和种族匹配对照。干预:没有。主要观察指标：SOHLH2基因变异分析。结果：在POF队列中发现了11个新的杂合变异体，但在匹配的对照组中没有。其中包括在4例中国POF患者中发现的p.Glu79Lys （n = 2例）、p.Glu105Gly和p.Thr321Pro非同义变体，以及在4例塞尔维亚女性中发现的p.Leu120Phe （n = 3例）和p.Leu204Phe。蛋白质比对显示，p.g ul79lys和p.g ul105gly涉及哺乳动物中高度保守的氨基酸，这两种氨基酸都被预测是有害的。在中国POF队列中发现的c - 210g > T位于核心启动子区域，该区域富含转录因子结合位点和CpG岛。在塞尔维亚队列中，最有可能产生有害影响的变异是c. 530+6T > G，预计它会影响RNA剪接并导致无义介导的转录本衰变。其他变异不太可能是有害的。干扰SOHLH2蛋白的表达、反激活或同源/异源二聚化可导致卵巢功能衰竭。总的来说，11种新变异中有4种似乎是对POF的合理解释；其他七种变体的可能性较小，但不能完全排除。结论：我们在中国和塞尔维亚血统的POF女性患者中发现了SOHLH2基因的新变异，这强烈表明SOHLH2在人类POF病因学中发挥了重要作用。(c) 2014年，美国生殖医学学会。
Objective: To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities.Design: Case-control genetic study.Setting: University hospitals.Patient(s): Chinese (364 cases) and Serbian (197 cases) women with nonsyndromic POF and ethnically matched controls.Intervention(s): None.Main Outcome Measure(s): Variation analysis of the SOHLH2 gene.Result(s): Eleven novel heterozygous variants were identified in cohorts of POF but were absent in matched controls. These included the nonsynonymous variants p.Glu79Lys (n = 2 cases), p.Glu105Gly, and p.Thr321Pro, which were found among four Chinese POF cases, and p.Leu120Phe (n = 3 cases) and p.Leu204Phe, which were found among four Serbian women. Protein alignments reveal that p.Glu79Lys and p.Glu105Gly involve amino acids highly conserved among mammals, both of which are predicted to be deleterious. The c.-210G > T found in the Chinese POF cohort lies in the core promoter region, which is enriched with transcription factor binding sites and CpG islands. In the Serbian cohort, the variant most likely to have a deleterious effect is c. 530+6T > G, which is predicted to affect RNA splicing and result in nonsense mediated decay of transcripts. The other variants are less likely to be deleterious. Disturbing the expression, transactivation or homo-/heterodimerization of the SOHLH2 protein could result in ovarian failure. Overall, four of the 11 novel variants seem plausible explanations for POF; the other seven variants are less likely but cannot be categorically excluded.Conclusion(s): Our identification of novel variants in the SOHLH2 gene, in women with POF of both Chinese and Serbian origin, strongly suggests an important role for SOHLH2 in human POF etiology. (c) 2014 by American Society for Reproductive Medicine.