2. Academic Validation
  3. TLE6 mutation causes the earliest known human embryonic lethality

TLE6 mutation causes the earliest known human embryonic lethality

  • Genome Biol. 2015 Nov 5;16:240. doi: 10.1186/s13059-015-0792-0.
Anas M Alazami 1,  Salma M Awad 2,  Serdar Coskun 3,  Saad Al-Hassan 4,  Hadia Hijazi 2,  Firdous M Abdulwahab 1,  Coralie Poizat 5,  Fowzan S Alkuraya 6 7
Affiliations

Affiliations

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 2 Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 3 Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia.
  • 4 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 5 Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. cpoizat99@kfshrc.edu.sa.
  • 6 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.
  • 7 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@Kfshrc.edu.sa.
PMID: 26537248 DOI: 10.1186/s13059-015-0792-0
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.

Conclusion: 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.

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