TLE6 mutation causes the earliest known human embryonic lethality. Issue 1 (December 2015)

• Record Type: Journal Article
• Authors: Alazami, Anas; Awad, Salma; Coskun, Serdar; Al-Hassan, Saad; Hijazi, Hadia; Abdulwahab, Firdous; Poizat, Coralie; Alkuraya, Fowzan
• Is Part Of: Genome biology. Volume 16:Issue 1(2015)
• Page Start: 1
• Page End: 8
• Publication Date: 2015-12
• Subjects: Mendelian -- Embryonic lethal -- Subcortical maternal complex -- Infertility; Genomes -- Periodicals; Biology -- Periodicals; Molecular biology -- Periodicals; 572.8633
• DOI: 10.1186/s13059-015-0792-0
• Languages: English
• ISSNs: 1474-760X

Abstract

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 inTLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouseTle6 mutants, embryos from female patients who are homozygous for theTLE6 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, theTLE6 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 theTLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype.