Novel mutations in VANGL1 in neural tube defects

Abstract

Neural tube defects (NTDs) are severe congenital malformations caused by failure of the neural tube to close during neurulation. Their etiology is complex involving both environmental and genetic factors. We have recently reported three mutations in the planar cell polarity gene VANGL1 associated with NTDs. The aim of the present study was to define the role of VANGL1 genetic variants in the development of NTDs in a large cohort of various ethnic origins. We identified five novel missense variants in VANGL1, p.Ser83Leu, p.Phe153Ser, p.Arg181Gln, p.Leu202Phe and p.Ala404Ser, occurring in sporadic and familial cases of spinal dysraphisms. All five variants affect evolutionary conserved residues and are absent from all controls analyzed. This study provides further evidence supporting the role of VANGL1 as a risk factor in the development of spinal NTDs.

Figure 1

Novel VANGL1 mutations in NTD patients. (A) A topological model of VANGL1 protein is shown with the approximate positions of the five variants p.Ser83Leu, p.Phe153Ser, p.Arg181Gln, p.Leu202Phe and p.Ala404Ser indicated in boxes. PDZBM: PDZ domain binding motif. (B) A partial alignment of human VANGL1 with 11 other vertebrate and invertebrate Vangl/Stbm sequences. Residues conserved between VANGL1 and other family members are highlighted. The VANGL1 variants found in NTD patients affect conserved residues (indicated by arrows). Accession numbers: human VANGL1 (hVANGL1), NP_620409; , dog Vangl1 (doVangl1), XP_857378; mouse Vangl1 (mVangl1), NP_808213; chicken Vangl1 (chVangl1), XP_001232441; human VANGL2 (hVANGL2), NP_065068; mouse Vangl2 (mVangl2), NP_277044, frog Vangl2 (xVangl2), AAK70879; zebrafishVangl2 (zVangl2), NP_705960; zebrafishVangl1 (zVangl1), AAQ84560; Drosophila Stbm (dStbm), NP_477177; African malaria mosquito Stbm (maStbm), EAA00250; C. elegans Stbm (ceStbm), NP_508500.