Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 91, Issue 3, Pages 541-547Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2012.07.009
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Funding
- Telethon Network Genetic Biobanks [GTB07001F]
- Manton Center for Orphan Disease Research
- National Institutes of Health (NIH) (National Institute of Child Health & Human Development [K99/R00, K99HD067379]
- Clinical Investigator Training Program at Harvard-MIT Health Science and Technology
- Nancy Lurie Marks Junior Faculty MeRIT Fellowship
- NIH (National Institute of Neurological Disorders and Stroke) [R01NS035129]
- NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases) [R01AR044345]
- Muscular Dystrophy Association
- William Randolph Hearst Fund
- Intellectual and Developmental Disabilities Research Centers [P30HD19655]
- NIH
- American Recovery & Reinvestment Act (National Institute of Mental Health) [RC2MH089952]
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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.
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