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Identification of Novel CELSR1 Mutations in Spina Bifida
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 p...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954890/ https://www.ncbi.nlm.nih.gov/pubmed/24632739 http://dx.doi.org/10.1371/journal.pone.0092207 |
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author | Lei, Yunping Zhu, Huiping Yang, Wei Ross, M. Elizabeth Shaw, Gary M. Finnell, Richard H. |
author_facet | Lei, Yunping Zhu, Huiping Yang, Wei Ross, M. Elizabeth Shaw, Gary M. Finnell, Richard H. |
author_sort | Lei, Yunping |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3954890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39548902014-03-18 Identification of Novel CELSR1 Mutations in Spina Bifida Lei, Yunping Zhu, Huiping Yang, Wei Ross, M. Elizabeth Shaw, Gary M. Finnell, Richard H. PLoS One Research Article 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. Public Library of Science 2014-03-14 /pmc/articles/PMC3954890/ /pubmed/24632739 http://dx.doi.org/10.1371/journal.pone.0092207 Text en © 2014 Lei et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Lei, Yunping Zhu, Huiping Yang, Wei Ross, M. Elizabeth Shaw, Gary M. Finnell, Richard H. Identification of Novel CELSR1 Mutations in Spina Bifida |
title | Identification of Novel CELSR1 Mutations in Spina Bifida |
title_full | Identification of Novel CELSR1 Mutations in Spina Bifida |
title_fullStr | Identification of Novel CELSR1 Mutations in Spina Bifida |
title_full_unstemmed | Identification of Novel CELSR1 Mutations in Spina Bifida |
title_short | Identification of Novel CELSR1 Mutations in Spina Bifida |
title_sort | identification of novel celsr1 mutations in spina bifida |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954890/ https://www.ncbi.nlm.nih.gov/pubmed/24632739 http://dx.doi.org/10.1371/journal.pone.0092207 |
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