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Carmel Toomes, James A. Poulter, David F. Gilmour, Ian M. Carr, Amanda J. Churchill, Eamonn Sheridan, Alex F. Markham, Sandra M. Bell, Manir Ali, Chris F. Inglehearn; Identification Of A New Gene Causing Non-syndromic Recessive Optic Atrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1637.
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Non-syndromic recessive optic atrophy is a rare but under reported form of optic neuropathy. To date only one gene (TMEM126A) and locus (ROA1 on 8q) have been identified. The purpose of this study was to identify the gene mutated in a large consanguineous pedigree with multiple cases of optic atrophy.
A whole genome autozygosity search was undertaken by processing DNA from affected family members with SNP microarrays and analysing the data using IBDfinder software. Candidate genes were sequenced using standard methods and splicing assayed using RT-PCR on RNA isolated from leucocytes.
Autozygosity mapping identified a locus on chromosome 20p spanning 6-Mb between D20S160 and D20S161. Multipoint linkage analysis gave a maximum lod score of 4.8. This locus contains 10 genes but screening of the coding exons and flanking splice sites of all genes in the locus failed to identify a mutation. However, further analysis of the available intronic sequence identified a potential splicing mutation located 79 bp before an exon. RT-PCR analysis confirmed that this resulted in the creation of a cryptic splice site and caused a frameshift mutation.
We have identified a new gene (ROA3) for non-syndromic recessive optic atrophy on chromosome 20p. The mutation appears to be hypomorphic and reduces the amount of protein produced rather than abolishing all functional protein. Correspondence: firstname.lastname@example.org
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