VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish

Annie Reynolds, Jonathan R. McDearmid, Stephanie Lachance, Patrizia De Marco, Elisa Merello, Valeria Capra, Philippe Gros, Pierre Drapeau, Zoha Kibar

Research output: Contribution to journalArticlepeer-review

Abstract

In humans, rare non-synonymous variants in the planar cell polarity gene VANGL1 are associated with neural tube defects (NTDs). These variants were hypothesized to be pathogenic based mainly on genetic studies in a large cohort of NTD patients. In this study, we validate the potential pathogenic effect of these mutations in vivo by investigating their effect on convergent extension in zebrafish. Knocking down the expression of tri, the ortholog of Vangl2, using an antisense morpholino (MO), as shown previously, led to a defective convergent extension (CE) manifested by a shortened body axis and widened somites. Co-injection of the human VANGL1 with the tri-MO was able to partially rescue the tri-MO induced phenotype in zebrafish. In contrast, co-injection of two human VANGL1 variants, p.Val239Ile and p.Met328Thr, failed to rescue this phenotype. We next carried out overexpression studies where we measured the ability of the human VANGL1 alleles to induce a CE phenotype when injected at high doses in zebrafish embryos. While overexpressing the wild-type allele led to a severely defective CE, overexpression of either p.Val239Ile or p.Met328Thr variant failed to do so. Results from both tri-MO knockdown/rescue results and overexpression assays suggest that these two variants most likely represent " loss-of-function" alleles that affect protein function during embryonic development. Our study demonstrates a high degree of functional conservation of VANGL genes across evolution and provides a model system for studying potential variants identified in human NTDs.

Original languageEnglish
Pages (from-to)385-392
Number of pages8
JournalMechanisms of Development
Volume127
Issue number7-8
DOIs
Publication statusPublished - Jul 2010

Keywords

  • Convergent extension
  • Neural tube defects
  • Planar cell polarity
  • VANGL genes
  • Zebrafish model

ASJC Scopus subject areas

  • Developmental Biology
  • Embryology

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