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N. Fuhrmann, M. V. Alavi, B. Wissinger; Genomic Rearrangements in the OPA1 Gene Are Frequent in Patients With Autosomal Dominant Optic Atrophy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5387. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Autosomal dominant Optic Atrophy (adOA) with a prevalence of up to 1:12.000 in Denmark is considered as the most frequent hereditary optic neuropathy. It is characterized by an insidious juvenile onset with loss of visual acuity, central visual field defects, colour discrimination disturbances and optic disc pallor. Previous publications as well as our own results associate adOA with mutations in the OPA1 gene in 32-70% of cases. Since these results were obtained by mutation screening techniques applying mainly PCR amplification and screening of the coding region, copy number variations of specific exons could not be detected. Therefore we performed Multiplex Ligation Probe Amplification (MLPA) in order to rule out such genomic rearrangements in OPA1.
Multiplex Ligation Probe Amplification (MLPA) is a relatively new technique for detection of genomic rearrangements. MLPA is a multiplex-PCR applying only one pair of primers for simultaneous, quantitative amplification. Comparison of the obtained fragment intensities allows detection of loss/gain of one or multiple exons, respectively. All obtained results in our study were confirmed by either long distance PCR and subsequent sequencing or heterozygousity analysis of flanking microsatellite markers.
Here we report for the first time on an initial screen for copy number variations in OPA1 in 37 independent adOA families using MLPA. With this approach we were able to identify genomic rearrangements in 7 of these families, including one deletion of exon 9 and 24, respectively, two different deletions of the complete OPA1 gene as well as a duplication of the exons 7-9, with the latter being present in three unrelated families.
Our findings show that gross genomic aberrations at the OPA1 gene locus are frequent in adOA (about 12.8%) and substantially contribute to the spectrum and prevalence of OPA1 mutations in adOA patients. Our findings of two different deletions of the complete coding region of OPA1 further strengthen the hypothesis of haploinsufficiency being the underlying pathomechanism in OPA1 gene related adOA and show that genomic rearrangements in dominantly inherited diseases are still underestimated to date.
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