FZD6is a novel gene for human neural tube defects

Abstract

Neural tube defects (NTDs) are severe malformations of the central nervous system, affecting 1 of 1,000 live births. Mouse models were instrumental in defining the signaling pathways defective in NTDs, including the planar cell polarity (PCP), also called noncanonical Frizzled/Disheveled pathway. Based on the highly penetrant occurrence of NTDs in double Fzd3/Fzd6−/− mutant mice, we investigated the role of the human orthologues, FZD3 and FZD6, by resequencing a cohort of 473 NTDs patients and 639 ethnically matched controls. While we could not demonstrate a significant contribution of FZD3 gene, we identified five rare FZD6 variants that were absent in all controls and predicted to have a functional effect by computational analysis: one de novo frameshift mutation (c.1843_1844insA), three missense changes (p.Arg405Gln, p.Arg511Cys p.Arg511His), and one substitution (c.*20C>T) affecting the 3′-untranslated region (UTR) of the gene. The overall rate of predicted deleterious variants of FZD6 was 5.1-fold higher in cases compared to controls, resulting in a significantly increased NTDs mutation burden. This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs. Hum Mutat 33:384–390, 2012. © 2011 Wiley Periodicals, Inc.

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.…”

Multiple roles of Ulk4 in neurogenesis and brain function

“…Mutations of human FZD6 are 5-fold enriched for neural tube defects, and Fzd3 ¡/¡ /Fzd6 ¡/¡ mice are associated with neural tube defects. 21 Wnt target genes are also dys-regulated in Ulk4 mutants. For example, Nr5a2 is involved in maintenance of the stemness of embryonic stem cells but reduced in Ulk4 mutants.…”

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

“…However, studies have verified that formation of the neural tube is directly correlated with the orientation of cell division and reduction of migration, in which one of the key factors is the regulation of the PCP pathway (Wang and Nathans, 2007). The impact of VANGL1 and FZD on neural tube formation is well-known in the PCP pathway (Wang et al, 2006;Kibar et al, 2007Kibar et al, , 2009Xu et al, 2011;De Marco et al, 2012;Cai et al, 2013).…”

“…FZD3 and FZD6 influence neural tube formation (Wang et al, 2006;De Marco et al, 2012). The FZD3 gene is located on chromosome 8p21, encoding protein composed of 666 amino acids, and its DNA sequence spans 70 kb; The FZD6 gene is located on chromosome 8q22.3-q23.1, encoding protein composed of 706 amino acids, and its DNA sequence spans 34 kb.…”

“…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). Recent studies have shown that FZD3 and FZD6 are associated with NTDs (Wang et al, 2006;De Marco et al, 2012). Because they are core genes of the PCP pathway, VANGL1 FZD3/6 may influence NTDs.…”