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M. A. Walter, T. Footz, S. Dubois, V. Raymond; A POAG-Associated STI1 Variant is Functionally Deficient and Genetically Interacts With UTP21/WDR36. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2146.
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Glaucoma is a common neurodegenerative disease characterized by progressive irreversible blindness and frequently presents with increased intra-ocular pressure. A variety of loci have been linked to inherited forms of the most common subtype, primary open-angle glaucoma (POAG), including one on 5q22.1 that harbors the rRNA-processing gene WDR36. The occurrence of rare non-synonymous WDR36 sequence variants in normal control subjects supports the theory that the genetics of POAG is complex, where the normally late-onset disease would result from gene:gene and gene:environment interactions. We previously demonstrated that WDR36 mutations encode functional defects that affect cell growth when expressed in the homologous UTP21 gene in haploid yeast carrying a null mutation in a second gene, the co-chaperone STI1. Our aim is to investigate if STI1 directly acts as a modifier of WDR36 variation in POAG patients.
One novel POAG-exclusive non-synonymous amino acid variant was discovered in 1/139 patients (all heterozygous for WDR36 variants) who were screened by direct sequencing of STI1 coding exons. This patient was doubly heterozygous, for STI1(K434R) and WDR36(L25P). Yeast strains expressing mutant forms of yUTP21 in a sti1 null background were transformed with plasmids expressing the wild-type or K434R variants of hSTI1, and assayed for growth rate.
A yeast strain co-expressing yUTP21(D621G) - homologous to hWDR36(D658G) - and hSTI1(K434R) exhibited slower growth than strains with only wild-type or single-mutant constructs, indicating that hSTI1(K434R) is functionally deficient and synthetically interacts with yUTP21.
These results are consistent with WDR36 and STI1 being co-modifier genes affecting POAG susceptibility through polygenic modes of inheritance. Furthermore, we propose that the WDR36/UTP21-STI1 interaction has been conserved throughout evolution and participates in the regulation of ribosome assembly and/or stress responses that normally prevent glaucoma.
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