Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: Possible role in autosomal dominant retinitis pigmentosa

Rainald Schmidt-Kastner, Hideo Yamamoto, Duco Hamasaki, Hiroko Yamamoto, Jean-Marie A Parel, Christoph Schmitz, C. Kathy Dorey, Janet C. Blanks, Markus N. Preising

Research output: Contribution to journalArticle

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Abstract

Purpose: High oxygen consumption and cyclical changes related to dark-adaptation are characteristics of the outer retina. Oxygenation changes may contribute to the selective vulnerability of the retina in retinitis pigmentosa (RP) patients, especially for those forms involving genes with global cellular functions. Genes coding for components of the U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome stand out, because mutations in four genes cause RP, i.e., RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3), while there is no degeneration outside the retina despite global expression of these genes. With the assumption that variable oxygenation plays a role in RP forms related to pre-mRNA splicing and the retina and brain are similar, we searched a data collection of ischemia-hypoxia regulated genes of the brain for oxygen regulated genes of the U4/U6.U5 tri-snRNP complex. Methods: A database of ischemia-hypoxia response (IHR) genes in the brain was generated from gene expression profiling studies [n=24]. Public databases (NCBI) were searched for RP genes with global function that are expressed in the brain. From the IHR gene list, we extracted genes that were directly related to retinal degeneration through a listed mutation (OMIM, Retnet, RISN). The database was then examined for indirect links to RP forms affecting the U4/U6.U5 tri-snRNP complex by searching for IHR genes contributing to this complex. Potential expression of matched genes in the retina was ascertained using NEIBank. Immunohistochemistry was used to-localize a selected protein of the U4/ U6.U5 tri-snRNP complex in cynomolgus monkey and human retina specimens. Results: The approach identified genes that cause retinal degeneration (CNGB1, SEMA4A, RRG4) or developmental changes (SOX2) when mutated. One IHR gene, Pim1, is the immediate binding partner for PAP1 (RP9). Three IHR genes linked the U4/U6.U5 tri-snRNP complex to regulation by oxygenation: PRPF4; SART1, also known as 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP or as hypoxia associated factor (HAF); and LSM8, U6 snRNA-associated Sm-like protein. The 110 kDa SR-related protein was localized in all retinal cells including photoreceptors. Conclusions: Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors where oxygen consumption follows a circadian rhythm. If the U4/U6.U5 tri-snRP complex is already impaired by mutations in any of the four genes causing RP, it may be unable to follow properly the physiological demands of oxygenation which are mediated by the four hypoxia-regulated proteins emerging in this study. Selective vulnerability may involve complex combinations of widely expressed genes, specific cellular functions and local energy availability.

Original languageEnglish
Pages (from-to)125-135
Number of pages11
JournalMolecular Vision
Volume14
StatePublished - Jan 25 2008

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Retinitis Pigmentosa
U5 Small Nuclear Ribonucleoproteins
Genes
Retina
Ischemia
Retinal Degeneration
Brain
Databases
Hypoxia
Proteins
Oxygen Consumption
Mutation
Spliceosomes
Gene Components
Genetic Databases
Dark Adaptation
Gene Expression
Vertebrate Photoreceptor Cells
Macaca fascicularis
RNA Precursors

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Schmidt-Kastner, R., Yamamoto, H., Hamasaki, D., Yamamoto, H., Parel, J-M. A., Schmitz, C., ... Preising, M. N. (2008). Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: Possible role in autosomal dominant retinitis pigmentosa. Molecular Vision, 14, 125-135.

Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex : Possible role in autosomal dominant retinitis pigmentosa. / Schmidt-Kastner, Rainald; Yamamoto, Hideo; Hamasaki, Duco; Yamamoto, Hiroko; Parel, Jean-Marie A; Schmitz, Christoph; Dorey, C. Kathy; Blanks, Janet C.; Preising, Markus N.

In: Molecular Vision, Vol. 14, 25.01.2008, p. 125-135.

Research output: Contribution to journalArticle

Schmidt-Kastner, R, Yamamoto, H, Hamasaki, D, Yamamoto, H, Parel, J-MA, Schmitz, C, Dorey, CK, Blanks, JC & Preising, MN 2008, 'Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: Possible role in autosomal dominant retinitis pigmentosa', Molecular Vision, vol. 14, pp. 125-135.
Schmidt-Kastner, Rainald ; Yamamoto, Hideo ; Hamasaki, Duco ; Yamamoto, Hiroko ; Parel, Jean-Marie A ; Schmitz, Christoph ; Dorey, C. Kathy ; Blanks, Janet C. ; Preising, Markus N. / Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex : Possible role in autosomal dominant retinitis pigmentosa. In: Molecular Vision. 2008 ; Vol. 14. pp. 125-135.
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abstract = "Purpose: High oxygen consumption and cyclical changes related to dark-adaptation are characteristics of the outer retina. Oxygenation changes may contribute to the selective vulnerability of the retina in retinitis pigmentosa (RP) patients, especially for those forms involving genes with global cellular functions. Genes coding for components of the U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome stand out, because mutations in four genes cause RP, i.e., RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3), while there is no degeneration outside the retina despite global expression of these genes. With the assumption that variable oxygenation plays a role in RP forms related to pre-mRNA splicing and the retina and brain are similar, we searched a data collection of ischemia-hypoxia regulated genes of the brain for oxygen regulated genes of the U4/U6.U5 tri-snRNP complex. Methods: A database of ischemia-hypoxia response (IHR) genes in the brain was generated from gene expression profiling studies [n=24]. Public databases (NCBI) were searched for RP genes with global function that are expressed in the brain. From the IHR gene list, we extracted genes that were directly related to retinal degeneration through a listed mutation (OMIM, Retnet, RISN). The database was then examined for indirect links to RP forms affecting the U4/U6.U5 tri-snRNP complex by searching for IHR genes contributing to this complex. Potential expression of matched genes in the retina was ascertained using NEIBank. Immunohistochemistry was used to-localize a selected protein of the U4/ U6.U5 tri-snRNP complex in cynomolgus monkey and human retina specimens. Results: The approach identified genes that cause retinal degeneration (CNGB1, SEMA4A, RRG4) or developmental changes (SOX2) when mutated. One IHR gene, Pim1, is the immediate binding partner for PAP1 (RP9). Three IHR genes linked the U4/U6.U5 tri-snRNP complex to regulation by oxygenation: PRPF4; SART1, also known as 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP or as hypoxia associated factor (HAF); and LSM8, U6 snRNA-associated Sm-like protein. The 110 kDa SR-related protein was localized in all retinal cells including photoreceptors. Conclusions: Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors where oxygen consumption follows a circadian rhythm. If the U4/U6.U5 tri-snRP complex is already impaired by mutations in any of the four genes causing RP, it may be unable to follow properly the physiological demands of oxygenation which are mediated by the four hypoxia-regulated proteins emerging in this study. Selective vulnerability may involve complex combinations of widely expressed genes, specific cellular functions and local energy availability.",
author = "Rainald Schmidt-Kastner and Hideo Yamamoto and Duco Hamasaki and Hiroko Yamamoto and Parel, {Jean-Marie A} and Christoph Schmitz and Dorey, {C. Kathy} and Blanks, {Janet C.} and Preising, {Markus N.}",
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TY - JOUR

T1 - Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex

T2 - Possible role in autosomal dominant retinitis pigmentosa

AU - Schmidt-Kastner, Rainald

AU - Yamamoto, Hideo

AU - Hamasaki, Duco

AU - Yamamoto, Hiroko

AU - Parel, Jean-Marie A

AU - Schmitz, Christoph

AU - Dorey, C. Kathy

AU - Blanks, Janet C.

AU - Preising, Markus N.

PY - 2008/1/25

Y1 - 2008/1/25

N2 - Purpose: High oxygen consumption and cyclical changes related to dark-adaptation are characteristics of the outer retina. Oxygenation changes may contribute to the selective vulnerability of the retina in retinitis pigmentosa (RP) patients, especially for those forms involving genes with global cellular functions. Genes coding for components of the U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome stand out, because mutations in four genes cause RP, i.e., RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3), while there is no degeneration outside the retina despite global expression of these genes. With the assumption that variable oxygenation plays a role in RP forms related to pre-mRNA splicing and the retina and brain are similar, we searched a data collection of ischemia-hypoxia regulated genes of the brain for oxygen regulated genes of the U4/U6.U5 tri-snRNP complex. Methods: A database of ischemia-hypoxia response (IHR) genes in the brain was generated from gene expression profiling studies [n=24]. Public databases (NCBI) were searched for RP genes with global function that are expressed in the brain. From the IHR gene list, we extracted genes that were directly related to retinal degeneration through a listed mutation (OMIM, Retnet, RISN). The database was then examined for indirect links to RP forms affecting the U4/U6.U5 tri-snRNP complex by searching for IHR genes contributing to this complex. Potential expression of matched genes in the retina was ascertained using NEIBank. Immunohistochemistry was used to-localize a selected protein of the U4/ U6.U5 tri-snRNP complex in cynomolgus monkey and human retina specimens. Results: The approach identified genes that cause retinal degeneration (CNGB1, SEMA4A, RRG4) or developmental changes (SOX2) when mutated. One IHR gene, Pim1, is the immediate binding partner for PAP1 (RP9). Three IHR genes linked the U4/U6.U5 tri-snRNP complex to regulation by oxygenation: PRPF4; SART1, also known as 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP or as hypoxia associated factor (HAF); and LSM8, U6 snRNA-associated Sm-like protein. The 110 kDa SR-related protein was localized in all retinal cells including photoreceptors. Conclusions: Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors where oxygen consumption follows a circadian rhythm. If the U4/U6.U5 tri-snRP complex is already impaired by mutations in any of the four genes causing RP, it may be unable to follow properly the physiological demands of oxygenation which are mediated by the four hypoxia-regulated proteins emerging in this study. Selective vulnerability may involve complex combinations of widely expressed genes, specific cellular functions and local energy availability.

AB - Purpose: High oxygen consumption and cyclical changes related to dark-adaptation are characteristics of the outer retina. Oxygenation changes may contribute to the selective vulnerability of the retina in retinitis pigmentosa (RP) patients, especially for those forms involving genes with global cellular functions. Genes coding for components of the U4/U6.U5 tri small nuclear ribonucleoprotein (tri-snRNP) complex of the spliceosome stand out, because mutations in four genes cause RP, i.e., RP9 (PAP1), RP11 (PRPF31), RP13 (PRPF8), and RP18 (PRPF3), while there is no degeneration outside the retina despite global expression of these genes. With the assumption that variable oxygenation plays a role in RP forms related to pre-mRNA splicing and the retina and brain are similar, we searched a data collection of ischemia-hypoxia regulated genes of the brain for oxygen regulated genes of the U4/U6.U5 tri-snRNP complex. Methods: A database of ischemia-hypoxia response (IHR) genes in the brain was generated from gene expression profiling studies [n=24]. Public databases (NCBI) were searched for RP genes with global function that are expressed in the brain. From the IHR gene list, we extracted genes that were directly related to retinal degeneration through a listed mutation (OMIM, Retnet, RISN). The database was then examined for indirect links to RP forms affecting the U4/U6.U5 tri-snRNP complex by searching for IHR genes contributing to this complex. Potential expression of matched genes in the retina was ascertained using NEIBank. Immunohistochemistry was used to-localize a selected protein of the U4/ U6.U5 tri-snRNP complex in cynomolgus monkey and human retina specimens. Results: The approach identified genes that cause retinal degeneration (CNGB1, SEMA4A, RRG4) or developmental changes (SOX2) when mutated. One IHR gene, Pim1, is the immediate binding partner for PAP1 (RP9). Three IHR genes linked the U4/U6.U5 tri-snRNP complex to regulation by oxygenation: PRPF4; SART1, also known as 110 kDa SR-related protein of the U4/U6.U5 tri-snRNP or as hypoxia associated factor (HAF); and LSM8, U6 snRNA-associated Sm-like protein. The 110 kDa SR-related protein was localized in all retinal cells including photoreceptors. Conclusions: Regulation by changes in oxygenation within the U4/U6.U5 tri-snRP complex could be particularly important for photoreceptors where oxygen consumption follows a circadian rhythm. If the U4/U6.U5 tri-snRP complex is already impaired by mutations in any of the four genes causing RP, it may be unable to follow properly the physiological demands of oxygenation which are mediated by the four hypoxia-regulated proteins emerging in this study. Selective vulnerability may involve complex combinations of widely expressed genes, specific cellular functions and local energy availability.

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