Abstract
Autosomal Dominant Optic Atrophy (ADOA) is the most common dominantly inherited optic neuropathy. In the majority of patients it is caused by OPA1 mutations and those predicted to introduce a premature termination codon (PTC) are frequently detected. Transcripts containing PTC may be degraded by nonsense-mediated mRNA decay (NMD), however very little is known about an effect of OPA1 mutations on NMD activation. Here, using a combination of linkage analysis and DNA sequencing, we have identified a novel c.91C>T OPA1 mutation with a putative premature stop codon (Q31*), which segregated with ADOA in two Polish families. At the mRNA level we found no changes in the amount of OPA1 transcript among mutation carriers vs. non-carriers. Specific allele quantification revealed a considerable level of the OPA1 mutant transcript. Our study identifies a novel pathogenic OPA1 mutation and shows that it is located in the transcript region not prone for NMD activation. The data emphasizes the importance of analyzing how mutated genes are being processed in the cell. This gives an insight into the molecular mechanism of a genetic disease and promotes development of innovative therapeutic approaches.
Highlights
Autosomal Dominant Optic Atrophy (ADOA; OMIM: #165500) is the most common form of inherited optic neuropathy leading to progressive bilateral reduction of visual acuity, centrocecal scotomas of variable density, color vision deficits and temporal optic disc pallor, which begin in early childhood [1, 2]
In this study we have identified a novel nonsense mutation p.Q31Ã in the second exon of the OPA1 gene in all affected family members from two families and show that it exhibits a high penetrance (83%)
OPA1 p.Q31Ã mutation introduces a UAA stop codon supposedly with a high termination fidelity but it should be taken into account that the read-through capacity of a stop codon may be directly altered by adjacent sequences and/or indirectly by cell- and tissuespecific changes affecting the nonsense-mediated mRNA decay (NMD) activity and subsequently mRNA levels from which functional protein might be produced [11]
Summary
Autosomal Dominant Optic Atrophy (ADOA; OMIM: #165500) is the most common form of inherited optic neuropathy leading to progressive bilateral reduction of visual acuity, centrocecal scotomas of variable density, color vision deficits and temporal optic disc pallor, which begin in early childhood [1, 2]. Due to variable inter- and intrafamiliar expressivity of ADOA visual impairment may range from mild to severe [3,4,5]. In about 10–20% of ADOA cases a more severe ADOA “plus” phenotype (DOA+; OMIM: # 125250) with extra-ophthalmic. Novel p.Gln31Ter OPA1 gene mutation in ADOA
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