Human Molecular Genetics Advance Access originally published online on January 15, 2009
Human Molecular Genetics 2009 18(7):1276-1287; doi:10.1093/hmg/ddp027
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Glaucoma-associated WDR36 variants encode functional defects in a yeast model system
1 Department of Medical Genetics, University of Alberta, 8-39 Medical Sciences Building, Edmonton, AB, Canada T6G 2H7 2 Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA 3 Laboratory of Ocular Genetics and Genomics, Laval University Hospital (CHUL) Research Center, 2705 Laurier Boulevard, Québec City, QC, Canada G1V 4G2
* To whom correspondence should be addressed. Tel: +1 780 4924172; Fax: +1 780 4921998; Email: mwalter{at}ualberta.ca
Received December 3, 2008; Revised January 7, 2009; Accepted January 13, 2009
Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. POAG is associated with a characteristic progression of changes to ocular morphology and degeneration at the optic nerve head with the loss of visual fields. Physical mapping efforts identified genomic loci in which to search for causative POAG gene mutations. WDR36, at locus GLC1G, was initially identified as a gene with a low frequency of non-synonymous sequence variations that were exclusive to adult-onset POAG patients. It has since been shown that rare WDR36 sequence variants are also present in the normal population at similarly low frequencies. The lack of a consistent genotype:phenotype correlation prompted us to investigate the functional consequences of WDR36 sequence variations. WDR36 is involved in rRNA processing, a critical step in ribosome biogenesis, and is very similar to yeast Utp21p which is a member of the small subunit (SSU) processome complex responsible for maturation of 18S rRNA. We, therefore, developed a yeast model system to test the functional and phenotypic consequences of POAG-associated sequence variants introduced into UTP21. Alone, the POAG variants did not produce any significant defects in cell viability or rRNA processing. However, when combined with disruption of STI1 (which synthetically interacts with UTP21), 5 of the 11 tested variants had increased or decreased cell viability which corresponded to reduced or elevated levels of pre-rRNA, respectively. These results demonstrate that, in the correct genetic background, WDR36 sequence variants can lead to an altered cellular phenotype, supporting the theory that WDR36 participates in polygenic forms of glaucoma.