title: 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.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Seo
authors.forename: Yulia
authors.initials: Y
authors.lastname: Zilber
authors.forename: Sima
authors.initials: S
authors.lastname: Babayeva
authors.forename: Jiajia
authors.initials: J
authors.lastname: Liu
authors.forename: Paulina
authors.initials: P
authors.lastname: Kyriakopoulos
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.forename: Elena
authors.initials: E
authors.lastname: Torban
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D016764:Cell Polarity / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004285:Dogs; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy
chemical_list: D003598:Cytoskeletal Proteins; C544812:Fuz protein, mouse; D047908:Intracellular Signaling Peptides and Proteins