RRC ID 79096
Author Derrick CJ, Szenker-Ravi E, Santos-Ledo A, Alqahtani A, Yusof A, Eley L, Coleman AHL, Tohari S, Ng AY, Venkatesh B, Alharby E, Mansard L, Bonnet-Dupeyron MN, Roux AF, Vaché C, Roume J, Bouvagnet P, Almontashiri NAM, Henderson DJ, Reversade B, Chaudhry B.
Title Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish.
Journal 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.
Volume 33(2)
Pages 150-169
Published 2024-1-7
DOI 10.1093/hmg/ddad171
PII 7304122
PMID 37815931
PMC PMC10772043
MeSH Animals Cell Polarity / genetics Germ Cells / metabolism Germ-Line Mutation / genetics Heart Defects, Congenital* / genetics Humans Membrane Proteins / genetics Membrane Proteins / metabolism Zebrafish* / genetics Zebrafish* / metabolism Zebrafish Proteins / genetics
IF 5.101
Zebrafish Tg(CM-isl1:GFP)rw0