Disease relevance of RPGRIP1

• Limited proteolysis differentially modulates the stability and subcellular localization of domains of RPGRIP1 that are distinctly affected by mutations in Leber's congenital amaurosis [1].
• Younger patients with an AIPL1 or RPGRIP1 variation were found to have severely reduced vision [2].
• RPGRIP is a strong candidate gene for causing human retinal degeneration [3].
• The combined information from expression analysis and chromosomal localization allowed for the identification of potential candidate genes for retinal diseases (CORD8, CORD9) and syndromic blindness/deafness/renal defects [4].

High impact information on RPGRIP1

• Most LCA-associated missense mutations in RPGRIP1 are located in a segment that encodes two C2 domains [5].
• Previously published work showed that both proteins, RPGR and RPGRIP1, are present in the ciliary structure that connects the inner and outer segments of rod and cone photoreceptors [6].
• Patients with RPGRIP1 mutations have a degeneration of both rod and cone photoreceptors, and, early in life, they experience a severe loss of central acuity, which leads to nystagmus [6].
• RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin [7].
• These results support distinct but complementary functions of RPGRIP1 isoforms in cytoskeletal-mediated processes in photoreceptors and amacrine neurons, and may explain the Leber phenotype linked to RPGRIP1 mutations in humans [8].

Biological context of RPGRIP1

• This model revealed a potential Ca2+-binding site that was predicted to be disrupted by a missense mutation in RPGRIP1, which was previously identified in an LCA patient [5].
• The human and bovine RPGRIP1 undergo alternative splicing [9].
• RPGRIP1 encompasses 24 coding exons, nine of which are first described here with their corresponding exon-intron boundaries [10].
• The tissue-specific expression of RPGRIP explains why mutations in the ubiquitously expressed RPGR confer a photoreceptor-specific phenotype [11].
• Using the newly available canine genome sequence we sequenced RPGRIP1 in affected and carrier MLHDs and identified a 44-nucleotide insertion in exon 2 that alters the reading frame and introduces a premature stop codon [12].

Anatomical context of RPGRIP1

• Moreover, recent reports are seemingly in disagreement on the localization of RPGR and RPGRIP in photoreceptors [13].
• RPGRIP is also expressed in other neurons such as amacrine cells [13].
• Here, we show that in cultured mammalian cells both RPGR(ORF15) and RPGRIP1 localize to centrioles [7].
• RPGRIP is the only protein known to localize specifically in the photoreceptor connecting cilium [11].
• When over-expressed in heterologous cell lines, RPGRIP appears in insoluble punctate and filamentous structures [11].

Associations of RPGRIP1 with chemical compounds

• Based on the C2 domain of novel protein kinase C epsilon (PKC epsilon), we built a 3D-homology model for the C-terminal C2 domain of RPGRIP1 [5].

Physical interactions of RPGRIP1

• The ORF15 isoform of RPGR (RPGR(ORF15)) and RPGR interacting protein 1 (RPGRIP1) are mutated in a variety of retinal dystrophies but their functions are poorly understood [7].

Other interactions of RPGRIP1

• These results provide a clue for the retina-specific pathogenesis in RP3, and hint towards the involvement of RPGR and RPGRIP1 in mediating vesicular transport-associated processes [14].
• A reduced dark-adapted isolated rod ERG response and/or maximal combined cone and rod response was recorded in carriers with mutations in the AIPL1, GUCY2D, and RPGRIP1 genes [15].
• The polymorphic nature of three previously described (pathological) sequence changes in AIPL1, CRB1, and RPGRIP1 was established [16].
• Among the nucleoporins, RPGRIP1 isoforms selectively associate in vivo with RanBP2 (Nup358) [8].
• We mapped the cord1 locus to a region of canine chromosome CFA15 that is syntenic with a region of human chromosome 14 (HSA14q11.2) containing the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) gene [12].

Analytical, diagnostic and therapeutic context of RPGRIP1

• METHODS: Identification of alternative splice transcripts of murine and human RPGRIP1 was performed by reverse transcription-polymerase chain reaction (RT-PCR) [9].
• The murine rpgrip1 isoforms were analyzed by immunoblot and immunocytochemistry analysis of murine retinas and transient transfected cultured cells [9].

References