Glaucoma-associated WDR36 variants encode functional defects in a yeast model system

Tim K Footz; Jill L Johnson; Stéphane Dubois; Nicolas Boivin; Vincent Raymond; Michael A Walter

doi:10.1093/hmg/ddp027

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Glaucoma-associated WDR36 variants encode functional defects in a yeast model system

Journal article

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Glaucoma-associated WDR36 variants encode functional defects in a yeast model system

Tim K Footz, Jill L Johnson, Stéphane Dubois, Nicolas Boivin, Vincent Raymond and Michael A Walter

Human molecular genetics, Vol.18(7), pp.1276-1287

04/01/2009

DOI: https://doi.org/10.1093/hmg/ddp027

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https://hdl.handle.net/2376/109068

PMID: 19150991

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Abstract

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.

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Title: Glaucoma-associated WDR36 variants encode functional defects in a yeast model system
Creators: Tim K Footz - 1 Department of Medical Genetics, University of Alberta, 8-39 Medical Sciences Building, Edmonton, AB, Canada T6G 2H7
Jill L Johnson - 2 Department of Microbiology, Molecular Biology and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA
Stéphane Dubois - 3 Laboratory of Ocular Genetics and Genomics, Laval University Hospital (CHUL) Research Center, 2705 Laurier Boulevard, Québec City, QC, Canada G1V 4G2
Nicolas Boivin - 3 Laboratory of Ocular Genetics and Genomics, Laval University Hospital (CHUL) Research Center, 2705 Laurier Boulevard, Québec City, QC, Canada G1V 4G2
Vincent Raymond - 3 Laboratory of Ocular Genetics and Genomics, Laval University Hospital (CHUL) Research Center, 2705 Laurier Boulevard, Québec City, QC, Canada G1V 4G2
Michael A Walter - 1 Department of Medical Genetics, University of Alberta, 8-39 Medical Sciences Building, Edmonton, AB, Canada T6G 2H7
Publication Details: Human molecular genetics, Vol.18(7), pp.1276-1287
Academic Unit: UNKNOWN
Publisher: Oxford University Press
Identifiers: 99900547691901842
Language: English
Resource Type: Journal article