Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure

Fertil Steril. 2014 Apr;101(4):1104-1109.e6. doi: 10.1016/j.fertnstert.2014.01.001. Epub 2014 Feb 10.


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.

Keywords: Premature ovarian failure (POF); SOHLH2; ovarian function; primary ovarian insufficiency (POI); variation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Case-Control Studies
  • China / epidemiology
  • Female
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Middle Aged
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide / genetics*
  • Prevalence
  • Primary Ovarian Insufficiency / epidemiology*
  • Primary Ovarian Insufficiency / genetics*
  • Risk Assessment
  • Serbia / epidemiology


  • Basic Helix-Loop-Helix Transcription Factors
  • Genetic Markers
  • SOHLH2 protein, human