Dominant Optic Atrophy plus phenotype caused by a deep intronic mutation and a modifier variant in the OPA1 gene

Abstract

SummaryMutations in OPA1 are a common cause of dominant optic neuropathy (DOA). Recent studies suggest that ~20% of patients carrying OPA1 mutations have additional neurological deficits (DOAplus phenotype). Such patients frequently carry missense mutations in the GTPase domain of OPA1 suggesting a gain‐of‐function effect as a major mechanism. We and others recently reported a series of DOAplus patients with biallelic OPA1 mutations as an alternative disease mechanism. Notably most cases were compound heterozygous for a null allele and the Ile382Met variant. The latter is not per se pathogenic but rather acts as a hypomorphic modifier allele that reinforces phenotypic expression in patients with null mutations on the opposite allele. In one biallelic DOAplus family we identified a deep intronic mutation (DIM) that causes a constitutive activation and inclusion of a cryptic frameshift‐inducing exon into OPA1 mRNA. Consistent with the DIM representing a null allele we observed reduced OPA1 protein amounts to about 50% of normal. Applying antisense oligonucleotides targeting the splice acceptor site of the DIM in patient fibroblasts we could efficiently rescue splicing of the mutant mRNA and re‐establish intermediate OPA1 protein levels.