ArticleFrontiers in medicine2025
Identification of a novel TLE6 mutation linked to embryonic arrest and limited rescue by mRNA supplementation.
Article in Frontiers in medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Novel biallelic PATL2 variants causing predominant germinal vesicle arrest and recurrent ART failure: expanded mutational spectrum and evidence-based reproductive counseling guidance.Journal of assisted reproduction and genetics · 2026Article
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7 authors.
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Abstract
Background: The subcortical maternal complex (SCMC) orchestrates early embryogenesis; TLE6, a core SCMC component, stabilizes the complex and regulates cytoskeletal dynamics during the oocyte-to-embryo transition. Pathogenic TLE6 variants are associated with pre-implantation arrest and infertility, but the mutational spectrum and rescue strategies remain incompletely defined. This study aims to describe a case of embryonic arrest associated with a novel homozygous TLE6 variant, elucidate its pathogenic mechanism, and evaluate an mRNA add-back rescue approach. Materials and methods: A case of primary infertility with repeated IVF failure underwent whole-exome sequencing, followed by confirmatory Sanger sequencing performed in the proband and parents. The variant function was assessed using a minigene splicing assay, Mutalyzer prediction, and structural modeling. A CRISPR/Cas9 Tle6 mouse model was evaluated for developmental consequences. Wild-type Tle6 mRNA was microinjected into mutant zygotes to test its rescue potential. Results: A novel homozygous splice-region variant in TLE6 (NM_001143986.1: exon7: c.286-7G > A) was identified, with both parents confirmed as heterozygous carriers. The minigene assay showed aberrant splicing with a 5-nucleotide insertion, producing a frameshift and premature truncation. Structural modeling predicted the loss of the C-terminal domain essential for SCMC integrity. The Tle6 mutant mouse recapitulated cleavage-stage arrest with reduced blastocyst formation. Zygotic add-back of wild-type Tle6 mRNA yielded only limited improvement, with persistent developmental failure. Conclusion: These findings expand the TLE6 variant spectrum and support a loss-of-function mechanism causing embryonic arrest through SCMC disruption. Acute zygotic mRNA supplementation was insufficient to restore developmental competence, indicating the need for alternative or early-stage interventions and informing genetic counseling for affected families.
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