OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy

Abstract

Purpose: Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease. Methods: To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means. Results: Seven new pathogenic OPA1 mutations were found.Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus.Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients.Conclusions: Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases. Genet Med 2006:8(4):217-225.

Mitochondrial oxidative phosphorylation in autosomal dominant optic atrophy

“…All patients in this study were examined by two experienced neuro-ophthalmologists (NJN, VB) and had clinical symptoms, age of onset, and family histories typical for ADOA, as described previously [ 24 ]. Informed consent was obtained from each study participant using an institutional IRB approved consent form.…”

“…Informed consent was obtained from each study participant using an institutional IRB approved consent form. OPA1 exons and intron/exon junctions were sequenced for all patients and a complete characterization of the ADOA-associated OPA1 variants have been described in detail in [ 24 ]. None harbored known LHON mtDNA mutations.…”

“…In a previous publication, we reported seven novel pathological OPA1 mutations in a cohort of 30 patients diagnosed with ADOA [ 24 ]. Lymphoblast cell lines were established from blood samples taken from six of the seven patients bearing novel OPA1 disease variants (referred to as OPA1 -positive) and from ten ADOA patients without OPA1 mutations (referred to as OPA1 -negative) (see Table 1 ).…”

Mitochondrial Optic Neuropathies: How Two Genomes may Kill the Same Cell Type?

“…Concerning DOA, the recent availability of genetic analysis enlightened the issue of incomplete penetrance and variability of clinical expressivity [68], suggesting that, as for LHON, also in the case of DOA further genetic contribution may be relevant. Thus, genetic variability in the OPA1 gene itself and the influence of mtDNA haplogroup may be the first places to look [69]. Based on the current knowledge on the common pathomechanism of LHON and OPA1-linked DOA, we propose that a common pool of genes potentially relevant as modifiers in both disorders is represented by all genes involved in regulating the bioenergetic efficiency of respiratory chain, the buffering of ROS overproduction, the machinery of fission/fusion and the control of apoptosis.…”

The Neuro-ophthalmology of Mitochondrial Disease

“…Therefore, as in LHON, DOA likely has genetic, epigenetic, and environmental factors which modify its phenotypic expression. Background mtDNA haplogroup may have an influence on the expression of disease in at least one subset of DOA patients: OPA1-negative DOA patients were found to have a three-fold overrepresentation of mitochondrial haplogroup J versus controls in one study 78. The other genetic, epigenetic, and environmental factors affecting DOA expression remain to be elucidated.…”