Linked Life Data

20043994

Source:http://linkedlifedata.com/resource/pubmed/id/20043994

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7-8
pubmed:dateCreated
2010-6-23
pubmed:abstractText
In humans, rare non-synonymous variants in the planar cell polarity gene VANGL1 are associated with neural tube defects (NTDs). These variants were hypothesized to be pathogenic based mainly on genetic studies in a large cohort of NTD patients. In this study, we validate the potential pathogenic effect of these mutations in vivo by investigating their effect on convergent extension in zebrafish. Knocking down the expression of tri, the ortholog of Vangl2, using an antisense morpholino (MO), as shown previously, led to a defective convergent extension (CE) manifested by a shortened body axis and widened somites. Co-injection of the human VANGL1 with the tri-MO was able to partially rescue the tri-MO induced phenotype in zebrafish. In contrast, co-injection of two human VANGL1 variants, p.Val239Ile and p.Met328Thr, failed to rescue this phenotype. We next carried out overexpression studies where we measured the ability of the human VANGL1 alleles to induce a CE phenotype when injected at high doses in zebrafish embryos. While overexpressing the wild-type allele led to a severely defective CE, overexpression of either p.Val239Ile or p.Met328Thr variant failed to do so. Results from both tri-MO knockdown/rescue results and overexpression assays suggest that these two variants most likely represent "loss-of-function" alleles that affect protein function during embryonic development. Our study demonstrates a high degree of functional conservation of VANGL genes across evolution and provides a model system for studying potential variants identified in human NTDs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1872-6356
pubmed:author
pubmed:copyrightInfo
Copyright 2009 Elsevier Ireland Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
127
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
385-92
pubmed:meshHeading
pubmed:articleTitle
VANGL1 rare variants associated with neural tube defects affect convergent extension in zebrafish.
pubmed:affiliation
Department of Obstetrics and Gynecology, CHU Sainte Justine Research Center and University of Montreal, Montreal, Quebec, Canada H3T 1C5.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't