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. 2011 Jul;80(1):76-82.
doi: 10.1111/j.1399-0004.2010.01515.x. Epub 2010 Jul 22.

Contribution of VANGL2 mutations to isolated neural tube defects

Z Kibar  1 , S Salem, C M Bosoi, E Pauwels, P De Marco, E Merello, A G Bassuk, V Capra, P Gros
Affiliations

Contribution of VANGL2 mutations to isolated neural tube defects

Z Kibar et al. Clin Genet. 2011 Jul.

Abstract

Vangl2 was identified as the gene defective in the Looptail (Lp) mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity (PCP) pathway, also called the non-canonical Frizzled/Dishevelled pathway, which mediates the morphogenetic process of convergent extension essential for proper gastrulation and neural tube formation in vertebrates. Genetic defects in PCP signaling have strongly been associated with NTDs in mouse models. To assess the role of VANGL2 in the complex etiology of NTDs in humans, we resequenced this gene in a large multi-ethnic cohort of 673 familial and sporadic NTD patients, including 453 open spina bifida and 202 closed spinal NTD cases. Six novel rare missense mutations were identified in seven patients, five of which were affected with closed spinal NTDs. This suggests that VANGL2 mutations may predispose to NTDs in approximately 2.5% of closed spinal NTDs (5 in 202), at a frequency that is significantly different from that of 0.4% (2 in 453) detected in open spina bifida patients (p = 0.027). Our findings strongly implicate VANGL2 in the genetic causation of spinal NTDs in a subset of patients and provide additional evidence for a pathogenic role of PCP signaling in these malformations.

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Conflict of interest statement

Conflict of interest

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
VANGL2 mutations in NTD patients. (A) A topological model of VANGL2 protein is shown with the approximate positions of the six novel mutations identified in NTD patients. (B) A partial alignment of human VANGL2 with 8 other Vangl/Stbm sequences. Residues conserved between VANGL2 and other family members are highlighted. The VANGL2 variants found in NTD patients affect conserved residues (indicated by arrows). Accession numbers: human VANGL2 (hVANGL2), NP_065068; human VANGL1 (hVANGL1), NP_620409; taurus Vangl2 (tVangl2), XP_598791; mouse Vangl2 (mVangl2), NP_277044, frog Vangl2 (xVangl2), AAK70879; zebrafishVangl2 (zVangl2), NP_705960 and Drosophila Stbm (dStbm), NP_477177.
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