Center for Reproductive Medicine, Shandong Provincial Hospital, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
Department of Genetics, University of Leicester, Leicester, United Kingdom.
Fertil Steril. 2014 Apr;101(4):1104-1109.e6. doi: 10.1016/j.fertnstert.2014.01.001. Epub 2014 Feb 10.
To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities.
Case-control genetic study.
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.
确定 SOHLH2 基因变异是否与不同种族的人类卵巢早衰（POF）有关。
病例对照遗传研究。
大学医院。
非综合征性 POF 的中国（364 例）和塞尔维亚（197 例）女性患者及与之匹配的对照者。
无。
SOHLH2 基因的变异分析。
在 POF 队列中发现了 11 种新的杂合变异，但在匹配对照中不存在。其中包括在 4 例中国 POF 病例中发现的非同义变异 p.Glu79Lys（n = 2 例）、p.Glu105Gly 和 p.Thr321Pro，以及在 4 例塞尔维亚妇女中发现的 p.Leu120Phe（n = 3 例）和 p.Leu204Phe。蛋白序列比对显示 p.Glu79Lys 和 p.Glu105Gly 涉及哺乳动物高度保守的氨基酸，这两种变异均被预测为有害的。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，最有可能具有有害影响的变异是 c.530+6T>G，该变异预计会影响 RNA 剪接并导致转录本的无意义介导的衰变。其他变异不太可能具有有害影响。干扰 SOHLH2 蛋白的表达、反式激活或同源/异源二聚化可能导致卵巢衰竭。总的来说，11 种新变异中的 4 种似乎是 POF 的合理解释；其他 7 种变异不太可能，但不能明确排除。
我们在中国和塞尔维亚 POF 女性中发现了 SOHLH2 基因的新变异，这强烈表明 SOHLH2 在人类 POF 病因学中起重要作用。
