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Boris Rosin, Prasanthi Namburi, Muhammad Imran Khan, Frans P Cremers, Eyal Banin, Dror Sharon; A frameshift mutation in RDH12 causes autosomal dominant retinitis pigmentosa in families of Tunisian Jewish origin. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1004. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To characterize the genetic cause of disease and the clinical phenotype in patients with retinitis pigmentosa (RP) who belong to four apparently non-related families of Tunisian-Jewish origin with a dominant pattern of disease inheritance.
We performed genetic analysis using molecular inversion probes (MIPs) analysis and Sanger sequencing. Ocular and retinal function and structure were assessed by a full clinical ophthalmological exam, full field electroretinography, elecotrooculography and color vision testing as well as optical coherence tomography (Heidelberg Engineering GmbH), and wide-field pseudocolor and autofluorescent imaging (OPTOS system).
The pedigrees demonstrated an autosomal dominant inheritance pattern, with approximately half of the family members in each generation being affected. However, examination of the candidate genes for common autosomal dominant mutations causing RP did not yield a result. In order to obtain a genetic diagnosis, we performed MIPs analysis of 109 genes known to cause inherited retinal disease and identified a heterozygous frameshift mutation (c.759del, p.Phe254Leu*24) towards the end of the open reading frame of the RDH12 gene (NM_152443.2), coding for retinol dehydrogenase 12. All affected family members exhibited clinical and electrophysiological findings typical of RP. Notably, the onset of symptoms was considerably delayed and the severity reduced in comparison to autosomal recessive cases associated with variants in the RDH12 gene. This milder phenotype was also evident in the ffERG responses, with some of the patients retaining sizable dark-adapted white flash and cone-flicker responses well into the 5th decade of life.
All but one reported RDH12 mutations were previously demonstrated to cause autosomal recessive Leber's congenital amaurosis and early-onset RP. Here we describe the second RDH12 mutation causing an autosomal dominant inheritance pattern in families with relatively mild RP. The mutation we identified affects the same RDH12 region as the previously described dominant frameshift mutation. We hypothesize that due to the proximity to the stop codon, the mRNA encoded by these two frameshift alleles is not recognized by the nonsense-mediated mRNA-decay and therefore not degraded, resulting in the production of an abnormal RDH12 protein that is toxic to the photoreceptor cell.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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