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M. L. Ritz, E. DelBono, J. L. Wiggs; Genotype Phenotype Correlations for Recurrent OPA1 Mutations. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1666.
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OPA1 codes for a dynamin-related GTPase that functions in mitochondria. The protein is expressed in retinal ganglion cells as well as many other tissues. OPA1 DNA sequence changes have been identified in patients with a wide range of phenotypes including autosomal dominant optic atrophy, low tension glaucoma and a syndrome of optic atrophy and sensorineural hearing loss. Of the more than 100 OPA1 mutations reported, only 27 have been reported more than once, and only two mutations have been reported more than twice. The 2708 delTTAG deletion is the most frequent mutation with at least 30 occurrences. The purpose of this study is to describe the clinical characteristics of a patient with optic atrophy and a de novo 2708 delTTAG mutation, and evaluate genotype phenotype correlations for the recurrent OPA1 mutations.
A patient with optic atrophy and unaffected family members were evaluated for OPA1 mutations. All 28 exons of the OPA1 gene were screened for mutations by PCR amplification and direct genomic sequencing. Sequence was analyzed using Vector NTI software and DNA sequence variants were confirmed using reverse sequence primers.
The proband was diagnosed with optic atrophy at age five. There was no family history and all other family members including his parents were assymtomatic. The proband did not have systemic abnormalities or hearing defects. Screening of the OPA1 gene identified a four base pair deletion in exon 27 (del2708TTAG) in the patient but not in either of his parents indicating that a de novo mutation event occurred. Previous reports of the del2708TTAG deletion in at least 30 patients indicate that this is a mutation hot spot. Most individuals carrying the del2708TTAG deletion have severe early onset disease.
Of the OPA1 mutations associated with optic atrophy, only two, R445H and del2708TTAG have occurred more than twice. These recurrent mutations are the most prevalent and therefore the most important to understand clinically. The R445H mutation may represent a founder effect, while the del2708TTAG mutation is likely to recur because of a mutation hot spot in the gene. The R445H mutation is associated with a unique phenotype that includes sensorineural hearing loss. This study helps define the association of the del2708TTAG mutation with a severe early-onset phenotype, and also provides further support for the hypothesis that the recurrence of this mutations is secondary to a mutation hotspot.
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