Mitochondria haplogroups in patients with dominant optic atrophy

Abstract

Purpose: The most common inherited optic neuropathies are dominant optic atrophy (DOA) caused by mutations in OPA1 and Leber hereditary optic neuropathy (LHON) caused by mutations in mitochondrial DNA (mtDNA). Previous studies have suggested that background mtDNA haplogroups may affect LHON pathogenicity and expressivity, however, the role of mtDNA halogroups in DOA remains unexplored. This study aims to identify mtDNA haplogroups in OPA1-related optic atrophy patients and to investigate the impact of the haplogroups on the clinical phenotype.

Methods: Fifty-nine patients with the clinical diagnosis of primary optic atrophy were studied. Genomic DNA was evaluated by next generation sequencing using the Genetic Eye Disease (GEDi) diagnostic panel that covers 234 genes (including OPA1) as well as the entire mitochondrial genome. Patients with apparent homozygosity based on consecutive single nucleotide polymorphisms were also evaluated for copy number variation (CNV) using Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. The mitochondrial haplogroup was determined using our custom halplogroup-defining tool Phy-Mer (Navarro-Gomez et al., submitted). The difference in clinical phenotype (both ocular and nonocular) among mtDNA haplogroups was tested with the ANOVA test for continuous data and with the chi-square test for categorical data.

Results: In the 59 optic atrophy cases, mtDNA haplogroup analysis identified 19 cases (32.2%) with haplogroup H, 10 cases (16.9%) with haplogroup U, and 8 cases (13.6%) with haplogroup J. Next generation sequencing and CNV analysis identified 21 patients (35.6%) with OPA1 disease-causing mutations and one patient (1.7%) with a primary LHON mutation (m.11778G>A). In the overall group (both with and without OPA1 mutations), significant differences in age of onset, visual acuity, and visual field among haplogroups was not observed (P > 0.05) although extra-ophthalmological abnormalities such as hearing loss and peripheral neuropathy tended to be more frequent in haplogroup J (42.9%) compared with haplogroups U/H (16.0%, P = 0.157). In the cases with OPA1 mutations (n = 21), we found significantly more extra-ocular abnormalities in haplogroup J cases (75.0%) compared to haplogroup U/H cases (0.0%, P = 0.0140).

Conclusions: This study showed a potential association between mtDNA haplogroup and extra-ocular findings in DOA with OPA1 mutation.