Human Molecular Genetics Advance Access published online on May 10, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn147
The primary open-angle glaucoma gene WDR36 functions in ribosomal-RNA processing and interacts with the p53 stress-response pathway
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI USA
* Corresponding Author: Brian A. Link, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Rd. BSB 405, Milwaukee, WI 53226, Email: blink{at}mcw.edu, Phone: 414 456 8072, Fax: 414 456 6517
Received February 25, 2008; Revised May 7, 2008; Accepted May 7, 2008
Primary open angle glaucoma (POAG) is a genetically complex neuropathy that affects retinal ganglion cells and is a leading cause of blindness worldwide. WDR36, a gene of unknown function, was recently identified as causative for POAG at locus GLC1G. Subsequent studies found disease associated variants in control populations, leaving the role of WDR36 in this disease unclear. To address this issue we determined the function of WDR36. We studied Wdr36 in zebrafish and found it is the functional homolog of yeast Utp21. Utp21 is cell essential and functions in the nucleolar processing of 18S rRNA, which is required for ribosome biogenesis. Evidence for functional homology comes from sequence alignment, ubiquitous expression, sub-cellular localization to the nucleolus, and loss of function phenotypes that include defects in 18S rRNA processing and abnormal nucleolar morphology. Additionally, we show loss of Wdr36 function leads to an activation of the p53 stress response pathway, suggesting that co-inheritance of defects in p53-pathway genes may influence the impact of WDR36 variants on POAG. While these results overall do not provide evidence for or against a role of WDR3 6 in POAG, they do provide important baseline information for future studies.