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Updated: Jan 13, 2026
Functional Manipulation of Maternal Gene Products Using In Vitro Oocyte Maturation in Zebrafish
Published on: April 22, 2017
Identification of a novel TLE6 mutation linked to embryonic arrest and limited rescue by mRNA supplementation
Ben Yuan1,2, Tian Xu3, Bingbing Luo1,2
1Department of Reproductive Medicine, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China.
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.
