Assessment of ASB10 Missense Variants in a German and Italian Cohort of Patients with Primary Open-Angle Glaucoma

Abstract

Purpose: : Mutationsin ASB10 have been recently reported as responsible for the primary open angle glaucoma (POAG) in the original GLC1F family. In this work we investigated the prevalence of ASB10 variants in patients with POAG, normal tension glaucoma (NTG) and juvenile primary open angle glaucoma (JOAG) and control subjects of German and Italian descent.

Methods: : Mutation screening was performed by sequencing the entire ASB10 coding region in 986 patients and 376 control subjects from Germany and 26 patients as well controls from Italy. We performed structural analysis based on homology modeling to explore possible consequence of non-synonymous variants on protein structure.

Results: : Altogether, we detected in the coding regions of the ASB10 gene 23 non synonymous variants manly distributed in the ankyrin-repeat domains of the protein. 7 of these were also present in control subjects. Molecular modeling predicts that 12 non synonymous variants have a destabilizing effect on the 3D-structure of the ankyrin-repeat domains. Motif analysis shows that other 7 non synonymous variants affect different phosphorylation sites. Taking into account only non synonymous variants with a predicted impaired function we could count a total of 19 variants in 55 patients (5,6%) and 8 healthy subjects (2,1%; p= 0,0057).

Conclusions: : Our findings extend the evidence that ASB10 is involved in the aetiology of glaucoma, although its exact role is still unknown. As for other genes associated to this disease, the large variability of rare variants supports the hypothesis for POAG of "common disease-rare variants". ASB10 gene mutations are associated with adult onset glaucoma both with high and low intraocular pressure and also with juvenile open angle glaucoma.

Keywords: genetics • gene screening