title: Identification of novel CELSR1 mutations in spina bifida.
abstract: Spina bifida is one of the most common neural tube defects (NTDs) with a complex etiology. Variants in planar cell polarity (PCP) genes have been associated with NTDs including spina bifida in both animal models and human cohorts. In this study, we sequenced all exons of CELSR1 in 192 spina bifida patients from a California population to determine the contribution of CELSR1 mutations in the studied population. Novel and rare variants identified in these patients were subsequently genotyped in 190 ethnically matched control individuals. Six missense mutations not found in controls were predicted to be deleterious by both SIFT and PolyPhen. Two TG dinucleotide repeat variants were individually detected in 2 spina bifida patients but not detected in controls. In vitro functional analysis showed that the two TG dinucleotide repeat variants not only changed subcellular localization of the CELSR1 protein, but also impaired the physical association between CELSR1 and VANGL2, and thus diminished the ability to recruit VANGL2 for cell-cell contact. In total, 3% of our spina bifida patients carry deleterious or predicted to be deleterious CELSR1 mutations. Our findings suggest that CELSR1 mutations contribute to the risk of spina bifida in a cohort of spina bifida patients from California.
authors.affiliation: Dell Pediatric Research Institute, Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Dell Pediatric Research Institute, Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Ross
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Dell Pediatric Research Institute, Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas, United States of America; Department of Chemistry, College of Natural Sciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004252:DNA Mutational Analysis; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D021381:Protein Transport; D016135:Spinal Dysraphism / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C454220:CELSR1 cadherin, human; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C468513:VANGL2 protein, human