Mutations in the planar cell polarity gene, Fuzzy, are associated with neural tube defects in humans

Abstract

Neural tube defects (NTDs) are a heterogeneous group of common severe congenital anomalies which affect 1-2 infants per 1000 births. Most genetic and/or environmental factors that contribute to the pathogenesis of human NTDs are unknown. Recently, however, pathogenic mutations of VANGL1 and VANGL2 genes have been associated with some cases of human NTDs. Vangl genes encode proteins of the planar cell polarity (PCP) pathway that regulates cell behavior during early stages of neural tube formation. Homozygous disruption of PCP genes in mice results in a spectrum of NTDs, including defects that affect the entire neural axis (craniorachischisis), cranial NTDs (exencephaly) and spina bifida. In this paper, we report the dynamic expression of another PCP gene, Fuzzy, during neural tube formation in mice. We also identify non-synonymous Fuzzy amino acid substitutions in some patients with NTDs and demonstrate that several of these Fuzzy mutations affect formation of primary cilia and ciliary length or affect directional cell movement. Since Fuzzy knockout mice exhibit both NTDs and defective primary cilia and Fuzzy is expressed in the emerging neural tube, we propose that mutations in Fuzzy may account for a subset of NTDs in humans.

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). …”

Planar Cell Polarity Pathway in Kidney Development and Function

“…However, Fuzzy and Inturned mutants also exhibit anomalies associated with defective cilia (e.g., cranial NTDs, polydactyly, and hydrochephalus). Mice with Fuzzy or Inturned mutations have short primary cilia [77,78,101,102]. Core PCP proteins are involved in a variety of ciliary functions; knockdown of Dishevelled in Xenopus reduces cilial number and length and randomizes the position of basal bodies in frog multiciliated skin cells [103].…”