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RPGR: Its role in photoreceptor physiology, human disease, and future therapies.

Megaw RD, Soares DC, Wright AF - Exp. Eye Res. (2015)

Bottom Line: It interacts with a wide variety of ciliary proteins, but its exact function is unknown.Recently, there have been important advances both in our understanding of RPGR function and towards the development of a therapy.This review summarises the existing literature on human RPGR function and dysfunction, and suggests that RPGR plays a role in the function of the ciliary gate, which controls access of both membrane and soluble proteins to the photoreceptor outer segment.

View Article: PubMed Central - PubMed

Affiliation: Scottish Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, United Kingdom. Electronic address: rolymegaw@ed.ac.uk.

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Major RPGR protein isoforms (constitutive RPGREx1-19 and RPGRORF15) domain schematic. (a) Domain architecture schematics for both major isoforms are shown drawn to scale. The seven blades (B1 to B7) that form the beta-propeller RCC1-like domain (RLD) encoded within Exons 1–10 in both major isoforms are indicated. The RPGREx1-19 C-terminal isoprenylation site (CAAX) is shown. The location of the RPGRORF15 Glutamate/Glycine-rich Domain and Basic Domain (BD) within the Open Reading Frame 15 are highlighted. All known disease-causing missense mutations (labelled), and a total of 52 known nonsense mutations specifically located within the Open Reading Frame 15 (vertical lines on domain schematic) are indicated. Mutation data was mapped from the Human Gene Mutation Database (Stenson et al., 2014) (accessed 27th May 2015). (b) The crystal structures of the RPGR RLD (blue) in complex with PDEδ (yellow) (Wätzlich et al., 2013) and RPGRIP1 (green) (Remans et al., 2014) are shown using PyMol (http://www.pymol.org) as surface representations with a transparency setting to highlight location of known missense mutations (red spheres, only alpha carbon atoms shown) on structure. PDEδ and RPGRIP1 interaction sites on the surface RPGR partially overlap (Remans et al., 2014).
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fig1: Major RPGR protein isoforms (constitutive RPGREx1-19 and RPGRORF15) domain schematic. (a) Domain architecture schematics for both major isoforms are shown drawn to scale. The seven blades (B1 to B7) that form the beta-propeller RCC1-like domain (RLD) encoded within Exons 1–10 in both major isoforms are indicated. The RPGREx1-19 C-terminal isoprenylation site (CAAX) is shown. The location of the RPGRORF15 Glutamate/Glycine-rich Domain and Basic Domain (BD) within the Open Reading Frame 15 are highlighted. All known disease-causing missense mutations (labelled), and a total of 52 known nonsense mutations specifically located within the Open Reading Frame 15 (vertical lines on domain schematic) are indicated. Mutation data was mapped from the Human Gene Mutation Database (Stenson et al., 2014) (accessed 27th May 2015). (b) The crystal structures of the RPGR RLD (blue) in complex with PDEδ (yellow) (Wätzlich et al., 2013) and RPGRIP1 (green) (Remans et al., 2014) are shown using PyMol (http://www.pymol.org) as surface representations with a transparency setting to highlight location of known missense mutations (red spheres, only alpha carbon atoms shown) on structure. PDEδ and RPGRIP1 interaction sites on the surface RPGR partially overlap (Remans et al., 2014).

Mentions: The RPGR gene is located on the short arm of the X chromosome (Xp21.1) (Meindl et al., 1996; Vervoort et al., 2000) and expresses at least 10 alternative transcripts of which 5 are predicted to be protein coding (Kirschner et al., 1999; Roepman et al., 2000; Neidhardt et al., 2007; Schmid et al., 2010). Expression of the major splice variants (see below) is at least partly driven by a TATA-less proximal promoter (Shu et al., 2012), which fits with the widespread expression of RPGR in adult mammalian tissues. The promoter contains 4 transcriptional start sites which may influence expression in different tissues and within which the transcription factor SP1 was shown to activate RPGR transcription. The protein products of the two major human RPGR alternative transcripts have been extensively studied (Fig. 1a) (Meindl et al., 1996; Roepman et al., 1996; Vervoort et al., 2000; Mavlyutov et al., 2002; Hong et al., 2003; Patil et al., 2012a).


RPGR: Its role in photoreceptor physiology, human disease, and future therapies.

Megaw RD, Soares DC, Wright AF - Exp. Eye Res. (2015)

Major RPGR protein isoforms (constitutive RPGREx1-19 and RPGRORF15) domain schematic. (a) Domain architecture schematics for both major isoforms are shown drawn to scale. The seven blades (B1 to B7) that form the beta-propeller RCC1-like domain (RLD) encoded within Exons 1–10 in both major isoforms are indicated. The RPGREx1-19 C-terminal isoprenylation site (CAAX) is shown. The location of the RPGRORF15 Glutamate/Glycine-rich Domain and Basic Domain (BD) within the Open Reading Frame 15 are highlighted. All known disease-causing missense mutations (labelled), and a total of 52 known nonsense mutations specifically located within the Open Reading Frame 15 (vertical lines on domain schematic) are indicated. Mutation data was mapped from the Human Gene Mutation Database (Stenson et al., 2014) (accessed 27th May 2015). (b) The crystal structures of the RPGR RLD (blue) in complex with PDEδ (yellow) (Wätzlich et al., 2013) and RPGRIP1 (green) (Remans et al., 2014) are shown using PyMol (http://www.pymol.org) as surface representations with a transparency setting to highlight location of known missense mutations (red spheres, only alpha carbon atoms shown) on structure. PDEδ and RPGRIP1 interaction sites on the surface RPGR partially overlap (Remans et al., 2014).
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Related In: Results  -  Collection

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fig1: Major RPGR protein isoforms (constitutive RPGREx1-19 and RPGRORF15) domain schematic. (a) Domain architecture schematics for both major isoforms are shown drawn to scale. The seven blades (B1 to B7) that form the beta-propeller RCC1-like domain (RLD) encoded within Exons 1–10 in both major isoforms are indicated. The RPGREx1-19 C-terminal isoprenylation site (CAAX) is shown. The location of the RPGRORF15 Glutamate/Glycine-rich Domain and Basic Domain (BD) within the Open Reading Frame 15 are highlighted. All known disease-causing missense mutations (labelled), and a total of 52 known nonsense mutations specifically located within the Open Reading Frame 15 (vertical lines on domain schematic) are indicated. Mutation data was mapped from the Human Gene Mutation Database (Stenson et al., 2014) (accessed 27th May 2015). (b) The crystal structures of the RPGR RLD (blue) in complex with PDEδ (yellow) (Wätzlich et al., 2013) and RPGRIP1 (green) (Remans et al., 2014) are shown using PyMol (http://www.pymol.org) as surface representations with a transparency setting to highlight location of known missense mutations (red spheres, only alpha carbon atoms shown) on structure. PDEδ and RPGRIP1 interaction sites on the surface RPGR partially overlap (Remans et al., 2014).
Mentions: The RPGR gene is located on the short arm of the X chromosome (Xp21.1) (Meindl et al., 1996; Vervoort et al., 2000) and expresses at least 10 alternative transcripts of which 5 are predicted to be protein coding (Kirschner et al., 1999; Roepman et al., 2000; Neidhardt et al., 2007; Schmid et al., 2010). Expression of the major splice variants (see below) is at least partly driven by a TATA-less proximal promoter (Shu et al., 2012), which fits with the widespread expression of RPGR in adult mammalian tissues. The promoter contains 4 transcriptional start sites which may influence expression in different tissues and within which the transcription factor SP1 was shown to activate RPGR transcription. The protein products of the two major human RPGR alternative transcripts have been extensively studied (Fig. 1a) (Meindl et al., 1996; Roepman et al., 1996; Vervoort et al., 2000; Mavlyutov et al., 2002; Hong et al., 2003; Patil et al., 2012a).

Bottom Line: It interacts with a wide variety of ciliary proteins, but its exact function is unknown.Recently, there have been important advances both in our understanding of RPGR function and towards the development of a therapy.This review summarises the existing literature on human RPGR function and dysfunction, and suggests that RPGR plays a role in the function of the ciliary gate, which controls access of both membrane and soluble proteins to the photoreceptor outer segment.

View Article: PubMed Central - PubMed

Affiliation: Scottish Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, United Kingdom. Electronic address: rolymegaw@ed.ac.uk.

Show MeSH
Related in: MedlinePlus