title: Nonsense mutation of EMX2 is potential causative for uterus didelphysis: first molecular explanation for isolated incomplete müllerian fusion.
abstract: OBJECTIVE
  To investigate the association between human empty spiracles homeobox 2 gene (EMX2) and incomplete müllerian fusion (IMF).
  
  
  METHODS
  Case-control study.
  
  
  METHODS
  University-based hospital.
  
  
  METHODS
  Cohort of 517 clinically well-characterized IMF cases and 563 control women.
  
  
  METHODS
  None.
  
  
  METHODS
  In cases and control women, direct sequencing of EMX2 exons and further functional studies; for functional studies, wild-type and mutant EMX2 expression plasmids constructed; human embryonic kidney cells (HEK293FT) transfected with empty vector, wild-type EMX2, mutant EMX2, and 1:1 combination (wild-type/mutant plasmids) with additional functional studies performed to clarify the deleterious effect of the novel mutation detected.
  
  
  RESULTS
  A novel nonsense mutation p.E142X was detected in one woman with a didelphic uterus (1 of 517, 0.19%). The results of Western blot analysis confirmed that the mutation caused a truncated protein as predicted, and functional studies proved that it resulted in a dominant negative effect.
  
  
  CONCLUSIONS
  The novel nonsense mutation we detected-EMX2, p.E142X- resulted in a dominant negative effect. The functional data were exemplified in HEK293FT cells. This reinforced the likelihood that EMX2 contributed to the pathophysiology of IMF. Although it is uncommon (0.19%), EMX2 is the first gene identified that if perturbed may cause isolated IMF.
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China; Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gao
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Ma
authors.affiliation: 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.forename: Joe Leigh
authors.initials: JL
authors.lastname: Simpson
authors.affiliation: Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, Jinan, People's Republic of China; Center for Reproductive Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China. Electronic address: chenzijiang@hotmail.com.
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D016022:Case-Control Studies; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009095:Mullerian Ducts / Q000002:abnormalities*; D014157:Transcription Factors / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000453:epidemiology / Q000235:genetics*; D014599:Uterus / Q000002:abnormalities*; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins
keywords: Dominant negative effect; EMX2; P63; incomplete müllerian fusion; müllerian duct anomalies