Purchase this article with an account.
R. G. Schmidt-Kastner, H. Yamamoto, D. Hamasaki, H. Yamamoto, J.-M. Parel, C. Schmitz, J. Blanks, M. Preising; The U4/U6.U5 Tri-Small Nuclear Riboprotein Complex Involved in Four Forms of Autosomal Dominant Retinitis Pigmentosa May Be Hypoxia-Regulated. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3713.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
High oxygen consumption and cyclical changes of oxygen levels related to dark-adaptation are critical for the normal function of photoreceptors. Changes in oxygenation may explain the selective vulnerability in retinitis pigmentosa (RP) for those forms involving genes with global cellular functions. Assuming similarity between the retina and brain, data mining of ischemia-hypoxia response (IHR) genes of the brain should identify oxygen regulated genes in protein complexes related to RP genes. The U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome was targeted for analysis, because mutations in four globally expressed genes cause RP (RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3)).
A database of IHR genes was generated from expression profiling studies in the rodent brain (n=24). Genes related to human retinal degeneration were extracted first using OMIM. The database was then examined for regulated genes of the U4/U6.U5 tri-snRNP complex, and retinal expression was ascertained (NEIBank). Immunohistochemistry localized one protein in the cynomolgus monkey (n=3) or human retina (n=1).
Three IHR genes were directly linked to retinal degeneration (CNGB1, SEMA4A, RRG4) and one indirectly through Pim1, the binding partner of PAP (RP9). Three IHR genes contributed to the U4/U6.U5 tri-snRNP complex, viz. a) PRPF4; b) SART1 / 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP / hypoxia associated factor (HAF); and c) LSM8. The 110 kDa SR-related protein was expressed in photoreceptors.
Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors, because oxygen consumption follows a circadian rhythm. If the complex is impaired by mutations in any of the four genes causing RP, it may be unable to follow the physiological demands of oxygenation mediated by the three genes identified here by data mining.
This PDF is available to Subscribers Only