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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of walker-warburg syndrome
American Journal of Human Genetics, Volume 91, No. 3, Year 2012
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Description
Whole-exome sequencing (WES), which analyzes the coding sequence of most annotated genes in the human genome, is an ideal approach to studying fully penetrant autosomal-recessive diseases, and it has been very powerful in identifying disease-causing mutations even when enrollment of affected individuals is limited by reduced survival. In this study, we combined WES with homozygosity analysis of consanguineous pedigrees, which are informative even when a single affected individual is available, to identify genetic mutations responsible for Walker-Warburg syndrome (WWS), a genetically heterogeneous autosomal-recessive disorder that severely affects the development of the brain, eyes, and muscle. Mutations in seven genes are known to cause WWS and explain 50%-60% of cases, but multiple additional genes are expected to be mutated because unexplained cases show suggestive linkage to diverse loci. Using WES in consanguineous WWS-affected families, we found multiple deleterious mutations in GTDC2 (also known as AGO61). GTDC2's predicted role as an uncharacterized glycosyltransferase is consistent with the function of other genes that are known to be mutated in WWS and that are involved in the glycosylation of the transmembrane receptor dystroglycan. Therefore, to explore the role of GTDC2 loss of function during development, we used morpholino-mediated knockdown of its zebrafish ortholog, gtdc2. We found that gtdc2 knockdown in zebrafish replicates all WWS features (hydrocephalus, ocular defects, and muscular dystrophy), strongly suggesting that GTDC2 mutations cause WWS. © 2012 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3512000/bin/mmc1.pdf
Authors & Co-Authors
Manzini, M. Chiara
United States, Boston
Boston Children's Hospital
Tambunan, Dimira E.
United States, Boston
Boston Children's Hospital
Hill, Robert Sean
United States, Boston
Boston Children's Hospital
Yu, Timothy W.
United States, Boston
Boston Children's Hospital
Maynard, Thomas Michael
United States, Washington, D.c.
The George Washington University School of Medicine and Health Sciences
Heinzen, Erin L.
United States, Durham
Duke University
Shianna, Kevin V.
United States, Durham
Duke University
Stevens, Christine R.
United States, Cambridge
Broad Institute
Partlow, Jennifer Neil
United States, Boston
Boston Children's Hospital
Barry, Brenda J.
United States, Boston
Boston Children's Hospital
Rodriguez, Jacqueline
United States, Boston
Boston Children's Hospital
Gupta, Vandana A.
United States, Boston
Boston Children's Hospital
Al-Qudah, Abdelkarim A.
Jordan, Amman
The University of Jordan
Eyaid, Wafaa M.
Saudi Arabia, Riyadh
King Abdulaziz Medical City - Riyadh
Friedman, Jan M.
Canada, Vancouver
The University of British Columbia
Canada, Vancouver
Bc Children's Hospital Research Institute
Salih, Mustafa Abdalla M.
Saudi Arabia, Riyadh
King Saud University
Clark, Robin Dawn
United States, Loma Linda
Loma Linda University
Moroni, Isabella
Italy, Milan
Foundation Istituto Di Ricovero e Cura a Carattere Scientifico National Tumour Institute Milan
Mora, Marina
Italy, Milan
Foundation Istituto Di Ricovero e Cura a Carattere Scientifico National Tumour Institute Milan
Beggs, Alan H.
United States, Boston
Boston Children's Hospital
Gabriel, Stacey Bolk
United States, Cambridge
Broad Institute
Walsh, Christopher A.
United States, Boston
Boston Children's Hospital
United States, Cambridge
Broad Institute
Statistics
Citations: 174
Authors: 22
Affiliations: 11
Identifiers
Doi:
10.1016/j.ajhg.2012.07.009
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Disability
Genetics And Genomics