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Kaylie Webb-Jones, alina radziwon, David G Birch, Ian M MacDonald; A novel SVA retrotransposon insertion in CHM results in loss of REP-1 protein causing choroideremia. Invest. Ophthalmol. Vis. Sci. 2019;60(9):412.
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Choroideremia is an X-linked retinal disease characterized by progressive atrophy of the choroid and retinal pigment epithelium. SVA (SINE/VNTR/Alu) elements, a type of non-autonomous retrotransposon are non-coding repetitive RNAs that can self-replicate and reinsert randomly into a gene, which can cause disease. Intragenic SVA insertions are reported as the mechanism underlying a number of diseases including retinitis pigmentosa (Shen 1994), but have never been reported in the CHM gene. Here we describe the phenotype and genotype of a choroideremia patient with a novel SVA insertion, and evaluate the SVA insertion’s impact on Rab Escort Protein 1 (REP-1).
An 11-year-old male with no family history of retinal disease, complaining of reduced acuity and decreased visual field underwent visual function exam including BCVA, ffERG, Octopus kinetic perimetry, SD-OCT, fundus auto-fluorescence imaging, and DNA sequence analysis of a panel of 266 retinal dystrophy genes (Retinal Dystrophy Panel Plus, Blueprint Genetics, San Francisco). A lymphoblastoid cell line was established and RNA was extracted for mRNA and immunoblot analysis of CHM transcript, and REP-1 respectively as previously described (Furgoch 2014).
Genetic analysis identified a novel hemizygous SVA insertion, c.97_98inSVA (p.Arg33insSVA), in exon 2 of CHM. Immunoblot analysis showed absence of REP-1 protein, while amplification from cDNA showed a smaller than expected product. Sequencing of the PCR product generated from cDNA showed skipping of all of exon 2, denoted r.50_116del. BCVA was 20/40 OD, 20/80 OS, visual fields were constricted to 20° with a large area of sensitivity in the temporal to inferior field, ffERG showed non-detectable rod responses and 30Hz cone flicker responses were reduced 60% in amplitude and significantly delayed (17.7 µV, 42 msec). Imaging showed photoreceptors limited to the fovea. A central area of hyper-fluorescence in the macula, along with a scalloped region of atrophy, was observed consistent with a diagnosis of choroideremia.
This case is the first report of a SVA insertion in the CHM gene associated with choroideremia. mRNA analysis and protein expression studies demonstrate skipping of exon 2 leading to absence of detectable protein expression. This patient manifested severe disease phenotype at an early age.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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