Distribution of OPA1-AS1 genetic variants in patients with optic atrophy

Abstract

Purpose: Mutations in OPA1 on chromosome 3q28 account for between 30 and 60% of dominant optic atrophy (DOA) cases. Although OPA1 mutation carriers frequently exhibit inter- and intra-familial phenotypic variability, factors impacting OPA1 variable expressivity are not yet known. OPA1 antisense RNA 1 (OPA1-AS1) is a long non-coding mRNA that extends from introns 5 to intron 7 of the OPA1 gene. OPA1-AS1 may function to regulate the expression of OPA1. This study aims to identify OPA1-AS1 genetic variants in optic atrophy patients and to investigate the impact of these variants on the clinical phenotype.

Methods: The study was approved by the Massachusetts Eye and Ear Infirmary Institutional Review Board. Fifty-four optic atrophy patients and 216 controls were studied. Genomic DNA was extracted from each subject and sequenced using primers designed to amplify all 3 exons in OPA1-AS1. The 10-20 basepairs of the flanking introns were also included in the targeted sequence. PLINK was used for estimation of haplotype frequencies and for haplotype association analysis. Multiple testing corrections were performed with 10,000 permutation tests. Linear regression was used to interrogate the association of OPA1-AS1 variants with continuous data under the assumption of an additive genetic effect.

Results: OPA1-AS1 sequencing identified four variants: rs9832709, rs3772393, and rs34307082 in exon 3 and rs9291059 in intron 1. Novel variants in OPA1-AS1 were not found. We found that an OPA1-AS1 haplotype was more common in optic atrophy cases (50.6%) than in controls (34.6%) (Corrected P = 0.0054). This haplotype frequency was similar in both cases with OPA1 mutations (58.3%) and in cases without OPA1 mutations (50.7%). There was an additive genetic effect of rs9832709 on age of disease diagnosis, suggesting that carriers of the C allele have an earlier age of onset (7.2 ± 4.5 years per allele). However, this was not statistically significant in the overall linear regression analysis (P = 0.113). Other phenotypic features, including visual acuity and visual field parameters, were not different among the genotype groups.

Conclusions: DOA patients have a different distribution of the variants in OPA1-AS1 compared to normal controls. While not statistically significant in this patient cohort, variants in OPA1-AS1 may influence the age of onset of optic atrophy. Further study will be required to confirm this finding.

Keywords: 613 neuro-ophthalmology: optic nerve • 539 genetics • 629 optic nerve