Yingying Qin1, Xue Jiao1, Raymond Dalgleish2, Svetlana Vujovic3, Jin Li4, Joe Leigh Simpson5, Farook Al-Azzawi6, Zi-Jiang Chen7. 1. 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. 2. Department of Genetics, University of Leicester, Leicester, United Kingdom. 3. Faculty of Medicine, University of Belgrade, Clinic of Endocrinology, Clinical Center of Serbia, Belgrade, Serbia. 4. Gynaecology Research Unit, University Hospitals of Leicester, Leicester, United Kingdom. 5. Research and Global Programs, March of Dimes Foundation, White Plains, New York; Human and Molecular Genetics, Obstetrics and Gynecology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida. 6. Gynaecology Research Unit, University Hospitals of Leicester, Leicester, United Kingdom. Electronic address: fa2@leicester.ac.uk. 7. 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; Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China. Electronic address: chenzijiang@hotmail.com.
Abstract
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.
OBJECTIVE: To determine whether variants in the SOHLH2 gene contribute to humanpremature 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 humanPOF etiology.
Authors: Nicolas Macaisne; Maria Sol Touzon; Aleksander Rajkovic; Judith L Yanowitz Journal: J Assist Reprod Genet Date: 2022-04-18 Impact factor: 3.357
Authors: JoAnne S Richards; Yi A Ren; Nicholes Candelaria; Jaye E Adams; Aleksandar Rajkovic Journal: Endocr Rev Date: 2018-02-01 Impact factor: 19.871