title: TLE6 mutation causes the earliest known human embryonic lethality.
abstract: BACKGROUND
  Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage.
  
  
  RESULTS
  In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex.
  
  
  CONCLUSIONS
  In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Awad
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Serdar
authors.initials: S
authors.lastname: Coskun
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Saad
authors.initials: S
authors.lastname: Al-Hassan
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hadia
authors.initials: H
authors.lastname: Hijazi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Firdous M
authors.initials: FM
authors.lastname: Abdulwahab
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. cpoizat99@kfshrc.edu.sa.
authors.forename: Coralie
authors.initials: C
authors.lastname: Poizat
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000328:Adult; D000818:Animals; D056970:Co-Repressor Proteins; D003241:Consanguinity; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005307:Fertilization in Vitro; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D008040:Genetic Linkage; D006801:Humans; D007247:Infertility, Female / Q000235:genetics* / Q000473:pathology; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D009154:Mutation; D009865:Oocytes / Q000254:growth & development* / Q000473:pathology; D010641:Phenotype; D012529:Saudi Arabia; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D056970:Co-Repressor Proteins; C530203:Tle6 protein, human; D014157:Transcription Factors