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Dominant Optic Atrophy plus phenotype caused by a deep intronic mutation and a modifier variant in the OPA 1 gene
Author(s) -
Wissinger B.,
Bonifert T.,
GonzalezMenendez I.,
Theurer Y.,
Synofzik M.,
Schoels L.
Publication year - 2015
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2015.0112
Subject(s) - frameshift mutation , biology , missense mutation , null allele , allele , genetics , exon , phenotype , mutation , rna splicing , mutant , gene , microbiology and biotechnology , rna
Summary Mutations in OPA 1 are a common cause of dominant optic neuropathy ( DOA ). Recent studies suggest that ~20% of patients carrying OPA 1 mutations have additional neurological deficits ( DOA plus phenotype). Such patients frequently carry missense mutations in the GTP ase domain of OPA 1 suggesting a gain‐of‐function effect as a major mechanism. We and others recently reported a series of DOA plus patients with biallelic OPA 1 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 DOA plus family we identified a deep intronic mutation ( DIM ) that causes a constitutive activation and inclusion of a cryptic frameshift‐inducing exon into OPA 1 mRNA . Consistent with the DIM representing a null allele we observed reduced OPA 1 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 OPA 1 protein levels.