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

Summary Mutations 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...

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Veröffentlicht in:Acta ophthalmologica (Oxford, England) England), 2015-10, Vol.93 (S255), p.n/a
Hauptverfasser: Wissinger, B., Bonifert, T., Gonzalez‐Menendez, I., Theurer, Y., Synofzik, M., Schoels, L.
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container_issue S255
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container_title Acta ophthalmologica (Oxford, England)
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creator Wissinger, B.
Bonifert, T.
Gonzalez‐Menendez, I.
Theurer, Y.
Synofzik, M.
Schoels, L.
description Summary Mutations 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.
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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. 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subjects Genotype & phenotype
Mutation
Ophthalmology
title Dominant Optic Atrophy plus phenotype caused by a deep intronic mutation and a modifier variant in the OPA1 gene
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