title: Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure.
abstract: OBJECTIVE
  To determine whether variants in the SOHLH2 gene contribute to human premature ovarian failure (POF) in different ethnicities.
  
  
  METHODS
  Case-control genetic study.
  
  
  METHODS
  University hospitals.
  
  
  METHODS
  Chinese (364 cases) and Serbian (197 cases) women with nonsyndromic POF and ethnically matched controls.
  
  
  METHODS
  None.
  
  
  METHODS
  Variation analysis of the SOHLH2 gene.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: 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.
authors: Yingying
authors: Y
authors: Qin
authors: 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.
authors: Xue
authors: X
authors: Jiao
authors: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors: Raymond
authors: R
authors: Dalgleish
authors: Faculty of Medicine, University of Belgrade, Clinic of Endocrinology, Clinical Center of Serbia, Belgrade, Serbia.
authors: Svetlana
authors: S
authors: Vujovic
authors: Gynaecology Research Unit, University Hospitals of Leicester, Leicester, United Kingdom.
authors: Jin
authors: J
authors: Li
authors: 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.
authors: Joe Leigh
authors: JL
authors: Simpson
authors: Gynaecology Research Unit, University Hospitals of Leicester, Leicester, United Kingdom. Electronic address: fa2@leicester.ac.uk.
authors: Farook
authors: F
authors: Al-Azzawi
authors: 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.
authors: Zi-Jiang
authors: ZJ
authors: Chen
mesh_terms: D000328:Adult; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D016649:Primary Ovarian Insufficiency / Q000453:epidemiology* / Q000235:genetics*; D018570:Risk Assessment; D055771:Serbia / Q000453:epidemiology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005819:Genetic Markers; C000588675:SOHLH2 protein, human
keywords: Premature ovarian failure (POF); SOHLH2; ovarian function; primary ovarian insufficiency (POI); variation