Novel mutations inVANGL1in 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.

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…The atypical cadherin, Fmi resides on both distal and proximal edges, where it binds neighboring cells through heomophilic interactions (Usui et al, 1999;Shimada et al, 2001). Xenopus, zebrafish and the mouse, the same set of 'core PCP' proteins has been shown to regulate a plethora of early developmental events ranging from convergent extension movements during gastrulation, orientation of cochlear hair cell in the ear, neural tube closure, oriented cell division, lung branching, hair follicle alignment and polarized ciliary beating in the trachea and brain ventricles (Goodrich andStrutt, 2011, Gray et al, 2011;Zallen, 2007;Bosoi et al, 2011;De Marco et al, 2012;Kibar et al, 2009;Kibar et al, 2007;Rida and Chen, 2009;Wang and Nathans, 2007;Yates and Dean, 2007;Segalen and Bellaïche, 2009;Vladar et al, 2012) ( Fig.1.6.4.1). In all cases local modulation of cytoskeleton is crucial for the proper conduct of these processes.…”

The intracellular carboxyl terminal domain of Vangl proteins contains plasma membrane targeting signals

“…21 in the N-terminus of this protein causes a loss of function in vivo. 14 In addition, the N-terminal segment of VANGL1/VANGL2 proteins harbors pathological variants (S83L and S84F) associated with sporadic cases of NTD 15,16 ; in particular, S84F maps to a Ser/Thr cluster that is phosphorylated in response to a Wnt5 signaling gradient required for PCP. 17 Hence, the amino terminal segment of Vangl proteins does not harbor critical determinants for PM targeting, but is nevertheless required for other functional aspects.…”

Gene-gene interaction between VANGL1, FZD3, and FZD6 correlated with neural tube defects in Han population of Northern China

“…The findings demonstrate rare variations in the PCP pathway make significant differences in the occurrence of NTDs and are involved in mutant genes, such as VANGL, FZD, CELSR1, and DVL, among others (Cai and Shi, 2014). Recent investigations both in China and other countries have demonstrated close relationships between VANGL1 and NTDs (Kibar et al, 2007;Kibar et al, 2009;Xu et al, 2011). There are both Ala116Pro variations in VANGL1 and an obviously short structure of the α-helix fragment after variation in Han population of Northern China (Cai et al, 2013).…”