Contribution of VANGL2 mutations to isolated neural tube defects

Abstract

Vangl2 was identified as the gene defective in the Looptail mouse model for neural tube defects (NTDs). This gene forms part of the planar cell polarity 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 multiethnic 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 7 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.

Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes

“…Each of these anomalies appears to have complex genetic and environmental influences (Dixon et al, 2011;Au et al, 2010;Wessels and Willems, 2010;Grosen et al, 2011). For rare patients with neural tube defects, a connection to PCP signaling comes from the finding of VANGL1, CELSR1, SCRIB and FUZ (the latter two are homologs of the Drosophila PCP genes scribbled and fuzzy, respectively) sequence variants (Kibar et al, 2007;Kibar et al, 2009;Kibar et al, 2011;Seo et al, 2011;Robinson et al, 2012). For human palate closure defects, there are statistically significant associations with single-nucleotide polymorphisms in the WNT3, WNT3A, WNT5A, WNT8A and WNT11 genes (Chiquet et al, 2008;Menezes et al, 2010;Yao et al, 2011;Mostowska et al, 2012).…”

Alternative Wnt Pathways and Receptors

“…Indeed, the developmental consequences of deregulated alternative Wnt signaling are substantial and include deficits in left/right patterning (Zhang and Levin 2009;Antic et al 2010;Song et al 2010), branching morphogenesis (Shabani et al 2008;Karner et al 2009;Yates et al 2010), cardiac outflow tract formation (Hamblet et al 2002;Phillips et al 2005;Etheridge et al 2008), intestinal elongation (Cervantes et al 2009;Yamada et al 2010), limb outgrowth (Yamaguchi et al 1999;Afzal et al 2000;van Bokhoven et al 2000;Schwarzer et al 2009;Person et al 2010;Gao et al 2011), and neural tube closure (Kibar et al 2001(Kibar et al , 2011Montcouquiol et al 2003;Seo et al 2011). …”

The roles of maternal Vangl2 and aPKC inXenopusoocyte and embryo patterning

“…In these experiments we focused first on the Xenopus homolog of Drosophila Van Gogh, Vangl2, because it plays pivotal roles in invertebrate and vertebrate planar polarized epithelia (reviewed in Vladar et al, 2009;Wansleeben and Meijlink, 2011), is expressed as a localized mRNA in Xenopus oocytes (see Fig. S2C in the supplementary material) and is the only PCP core component for which a mutation has been identified in human familial and sporadic cases of neural tube defects (Kibar et al, 2009;Kibar et al, 2011;Lei et al, 2011). We first examined the distribution of Vangl2 protein (Goto and Keller, 2002) in oocytes, by immunostaining with a Vangl2 specific antibody.…”