PUBLICATION

Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish

Authors
Derrick, C.J., Szenker-Ravi, E., Santos-Ledo, A., Alqahtani, A., Yusof, A., Eley, L., Coleman, A.H.L., Tohari, S., Ng, A.Y., Venkatesh, B., Alharby, E., Mansard, L., Bonnet-Dupeyron, M.N., Roux, A.F., Vaché, C., Roume, J., Bouvagnet, P., Almontashiri, N.A.M., Henderson, D.J., Reversade, B., Chaudhry, B.
ID
ZDB-PUB-231011-53
Date
2023
Source
Human molecular genetics   33(2): 150-169 (Journal)
Registered Authors
Chaudhry, Bill, Derrick, Chris, REVERSADE, Bruno, Roux, Stephanie, Venkatesh, Byrappa
Keywords
congenital heart defect, neural tube defect, planar cell polarity, variant of unknown significance, zebrafish
MeSH Terms
  • Humans
  • Animals
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Zebrafish*/genetics
  • Zebrafish*/metabolism
  • Cell Polarity/genetics
  • Germ Cells/metabolism
  • Germ-Line Mutation/genetics
  • Zebrafish Proteins/genetics
  • Heart Defects, Congenital*/genetics
(all 11)
PubMed
37815931 Full text @ Hum. Mol. Genet.
Abstract
Developmental studies have shown that the evolutionarily conserved Wnt planar cell polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala), and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
m209
    Point Mutation
    rw0TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      congenital heart diseaseTAS
      nonsyndromic deafnessTAS
      visceral heterotaxyTAS
      1 - 3 of 3
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      Sequence Targeting Reagents
      No data available
      Fish
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      GFPEFGGFP
      1 - 1 of 1
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      Mapping
      No data available