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.
Pubmed ID: 24632739 RIS Download
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International collaboration producing an extensive public catalog of human genetic variation, including SNPs and structural variants, and their haplotype contexts, in an effort to provide a foundation for investigating the relationship between genotype and phenotype. The genomes of about 2500 unidentified people from about 25 populations around the world were sequenced using next-generation sequencing technologies. Redundant sequencing on various platforms and by different groups of scientists of the same samples can be compared. The results of the study are freely and publicly accessible to researchers worldwide. The consortium identified the following populations whose DNA will be sequenced: Yoruba in Ibadan, Nigeria; Japanese in Tokyo; Chinese in Beijing; Utah residents with ancestry from northern and western Europe; Luhya in Webuye, Kenya; Maasai in Kinyawa, Kenya; Toscani in Italy; Gujarati Indians in Houston; Chinese in metropolitan Denver; people of Mexican ancestry in Los Angeles; and people of African ancestry in the southwestern United States. The goal Project is to find most genetic variants that have frequencies of at least 1% in the populations studied. Sequencing is still too expensive to deeply sequence the many samples being studied for this project. However, any particular region of the genome generally contains a limited number of haplotypes. Data can be combined across many samples to allow efficient detection of most of the variants in a region. The Project currently plans to sequence each sample to about 4X coverage; at this depth sequencing cannot provide the complete genotype of each sample, but should allow the detection of most variants with frequencies as low as 1%. Combining the data from 2500 samples should allow highly accurate estimation (imputation) of the variants and genotypes for each sample that were not seen directly by the light sequencing. All samples from the 1000 genomes are available as lymphoblastoid cell lines (LCLs) and LCL derived DNA from the Coriell Cell Repository as part of the NHGRI Catalog. The sequence and alignment data generated by the 1000genomes project is made available as quickly as possible via their mirrored ftp sites. ftp://ftp.1000genomes.ebi.ac.uk ftp://ftp-trace.ncbi.nlm.nih.gov/1000genomes
View all literature mentionsThe goal of the project is to discover novel genes and mechanisms contributing to heart, lung and blood disorders by pioneering the application of next-generation sequencing of the protein coding regions of the human genome across diverse, richly-phenotyped populations and to share these datasets and findings with the scientific community to extend and enrich the diagnosis, management and treatment of heart, lung and blood disorders. The groups participating and collaborating in the NHLBI GO ESP include: Seattle GO - University of Washington, Seattle, WA Broad GO - Broad Institute of MIT and Harvard, Cambridge, MA WHISP GO - Ohio State University Medical Center, Columbus, OH Lung GO - University of Washington, Seattle, WA WashU GO - Washington University, St. Louis, MO Heart GO - University of Virginia Health System, Charlottesville, VA ChargeS GO - University of Texas Health Sciences Center at Houston
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MDCK is a Spontaneously immortalized cell line with a species of origin Canis lupus familiaris
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