Reduced expression of the OPA1 gene due to a novel p.Q31X nonsense mutation leads to autosomal dominant optic atrophy

Abstract

Purpose: Autosomal dominant optic atrophy (ADOA) is the most prevalent dominantly inherited optic neuropathy. The aim of the study was to identify the genetic etiology of inherited optic neuropathy in a Polish family.

Methods: We report on a 2-generation Polish family with ADOA in which nine family members are affected. MRI and detailed ophthalmological examination with visual field and electrophysiological testing were performed. DNA and protein extracts were obtained from blood samples. Linkage to OPA1, the main ADOA locus, as well as sequencing of all OPA1 exons were conducted. Amplified fragments were analyzed on an automatic DNA sequencer. OPA1 expression was analyzed by Western blot.

Results: MRI and ophthalmological examination confirmed the diagnosis of bilateral optic neuropathy. Pattern visual evoked potentials (PVEP) presented abnormally delayed P100 wave latency. Pedigree analysis demonstrated a dominant mode of inheritance. Linkage studies revealed linkage to the major OPA1 locus in the investigated family. Sequencing of the OPA-1 gene identified a novel C-to-T transition in exon 2 predicting a premature stop codon (Q31X). The mutation co-segratated with the phenotype in this family. No other mutation was found in the OPA1 gene. Expression of OPA1 at the protein level was strongly reduced as compared to control samples from healthy individuals.

Conclusions: Occurrence of the premature termination codon at the beginning of the transcript, which leads to a strong reduction of OPA1 protein expression, confirms that ADOA in the investigated family is a consequence of OPA1 haploinsufficiency. The novel variant broadens the spectrum of the reported OPA1 mutations causing ADOA.

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