Identification of Novel CELSR1 Mutations in Spina Bifida

• Published in: PloS one Vol. 9; no. 3; p. e92207
• Main Authors: Lei, Yunping, Zhu, Huiping, Yang, Wei, Ross, M. Elizabeth, Shaw, Gary M., Finnell, Richard H.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.03.2014; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Auditory defects; Base Sequence; Biology and Life Sciences; Birth defects; Cadherins - genetics; Cadherins - metabolism; Cell adhesion; Cell Membrane - metabolism; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; Dogs; Drosophila; Etiology; Exons; Fetuses; Functional analysis; Genes; Genetic aspects; Genetic testing; Genomes; HEK293 Cells; Hispanic people; Human subjects; Humans; Infant; Insects; Intracellular Signaling Peptides and Proteins - metabolism; Localization; Madin Darby Canine Kidney Cells; Medical research; Medical screening; Medicine and Health Sciences; Membrane Proteins - metabolism; Mice; Missense mutation; Mutation; Neural tube defects; Newborn babies; Patients; Pediatrics; Polarity; Population studies; Predictive control; Protein Transport; Spina bifida; Spinal Dysraphism - genetics; Spinal Dysraphism - metabolism; Spinal Dysraphism - pathology; Studies
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092207

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.