title: Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker-Warburg syndrome.
abstract: 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.
authors.affiliation: Division of Genetics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
authors.forename: Dimira E
authors.initials: DE
authors.lastname: Tambunan
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Tim W
authors.initials: TW
authors.lastname: Yu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Maynard
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Christine R
authors.initials: CR
authors.lastname: Stevens
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rodriguez
authors.forename: Vandana A
authors.initials: VA
authors.lastname: Gupta
authors.forename: Abdel-Karim
authors.initials: AK
authors.lastname: Al-Qudah
authors.forename: Wafaa M
authors.initials: WM
authors.lastname: Eyaid
authors.forename: Jan M
authors.initials: JM
authors.lastname: Friedman
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Robin
authors.initials: R
authors.lastname: Clark
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D059472:Exome; D016695:Glycosyltransferases / Q000235:genetics*; D006801:Humans; D009154:Mutation; D058494:Walker-Warburg Syndrome / Q000235:genetics*
chemical_list: D016695:Glycosyltransferases; C576562:POMGNT2 protein, human