Abstract
Purpose: :
Open angle glaucoma (OAG) is primarily considered a complex disease arising from gene-gene and/or gene-environment interactions. Several studies suggested that one of the genes which caused mendelian forms of the disorder, WDR36, also act as a modifier gene. We recently observed in yeast, that mutations in UTP21 (the yeast homolog of human WDR36), which are homologous to glaucoma-associated variants in WDR36, accounted for cell growth defects resulting from altered protein function. These effects were mediated through essential interactions with the co-chaperone STI1. To assess if STI1 may be a co-modifier gene interacting with WDR36 on the severity of the glaucoma phenotype, we screened for STI1 variations in patients carrying WDR36 variants.
Methods: :
The 14 coding exons (2201 nt) and flanking introns of STI1 were screened by direct genomic sequencing in an average of 168 unrelated OAG patients per exon (with or without ocular hypertension) and in 56 investigated normal subjects. All participants were caucasians. 139 patients carried one WDR36 variation (WDR36+) while the other 21 were WDR36 wild-type. We further screened 42 patients in the huge CA French-Canadian family, all of them were double-variants as they harbored the myocilin K423E mutation and one (1) WDR36 variation, among them 19 were JOAG (age at onset below 25 years old) while the other 23 were POAG (age at onset above 35 years old).
Results: :
Overall, 6 sequence alterations were detected in 37 subjects. Five (5) of these encoded synonymous amino acid changes, R142R, T243T, Y248Y, A437A, K434R. The other variation was in intron 11, ivs11 + 10 T > G, in silico studies suggested that this variation did not change the splicing pattern of the STI1 gene. The overall prevalences of the variations showed a tendency to be decreased in the patient groups compared to the investigated normal group; 17/139 (12.2%) affected WDR36+; 3/21 (14.2 %) affected WDR36 wild-type; in the CA family 0/19 JOAG (0%) and 4/23 (17.4 %) POAG; 13/56 (23.2 %) investigated normal.
Conclusions: :
STI1 is a highly polymorphic gene. No amino acid changes were observed in the STI1 protein but, overall, the prevalence of synonymous variations was higher in controls than in glaucoma patients. Although this study does not suggest that STI1 is a co-modifier protein, additional experiments aimed at investigating if differences in STI1 mRNA turnover or expression level are required to further investigate if changes in STI1 levels may contribute to changes in the glaucoma phenotype.
Keywords: gene modifiers • genetics • optic nerve