Mutations in the Pre-mRNA Splicing-Factor GenesPRPF3,PRPF8, andPRPF31in Spanish Families with Autosomal Dominant Retinitis Pigmentosa

Martinez-Gimeno, María; Gamundi, María José; Hernán, Imma; Maseras, Miquel; Millá, Elena; Ayuso, Carmen; Garcı́a-Sandoval, Blanca; Beneyto, Magdalena; Vilela, Concha; Baiget, Montserrat; Antiñolo, Guillermo; Carballo, Miguel

doi:10.1167/iovs.02-0871

Cited by 81 publications

(73 citation statements)

References 28 publications

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“…retina. A severe form of this disease (RP13) was found to be associated with mutations in human PRP8 (McKie et al 2001;De Erkenez et al 2002;van Lith-Verhoeven et al 2002;Kondo et al 2003;Martinez-Gimeno et al 2003). The association of hPrp8p with a retinal-specific disorder was a surprising result, as Prp8 function is required in all cell types.…”

Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

“…The C-terminal 94-amino-acid region of hPrp8p interacts with the multifunctional PAI-2 protein, the significance of which is unclear (Fan et al 2004). Other RP13 mutations correspond to frameshifts that extend from residues h2298, 2315, 2325, 2331, and 2335 (the normal stop codon), all resulting in the introduction of nonconserved amino acids (De Erkenez et al 2002;Martinez-Gimeno et al 2003). In the case of the mutation of the stop codon, the protein extension may be deleterious, as the conserved sequences at the C terminus are unaffected.…”

Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

“…Three other splicing proteins, Prp3 (Chakarova et al 2002), Prp31 (Vithana et al 2001;Martinez-Gimeno et al 2003), and PAP-1 (Maita et al 2004(Maita et al , 2005, are also linked to Retinitis Pigmentosa. Like Prp8p, PAP-1, Prp31, and Prp3 are involved in formation of the U5·U4/U6 tri-snRNP (Anthony et al 1997;Makarova et al 2002).…”

Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

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Prp8 protein: At the heart of the spliceosome

Grainger¹,

Beggs²

2005

RNA

316

386

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Pre-messenger RNA (pre-mRNA) splicing is a central step in gene expression. Lying between transcription and protein synthesis, pre-mRNA splicing removes sequences (introns) that would otherwise disrupt the coding potential of intron-containing transcripts. This process takes place in the nucleus, catalyzed by a large RNA-protein complex called the spliceosome. Prp8p, one of the largest and most highly conserved of nuclear proteins, occupies a central position in the catalytic core of the spliceosome, and has been implicated in several crucial molecular rearrangements that occur there. Recently, Prp8p has also come under the spotlight for its role in the inherited human disease, Retinitis Pigmentosa.Prp8 is unique, having no obvious homology to other proteins; however, using bioinformatical analysis we reveal the presence of a conserved RNA recognition motif (RRM), an MPN/JAB domain and a putative nuclear localization signal (NLS). Here, we review biochemical and genetical data, mostly related to the human and yeast proteins, that describe Prp8's central role within the spliceosome and its molecular interactions during spliceosome formation, as splicing proceeds, and in post-splicing complexes. NOTE ON NOMENCLATUREIn this review, Prp8 and Prp8p represent the protein product of the wild-type PRP8 gene of Saccharomyces cerevisiae, while prp8-1 is an example of a mutant allele of the PRP8 gene. Human Prp8 protein is designated hPrp8, also known in the literature as PRPF8, PRPC8, p220, and 220K. In some places, to avoid confusion, yPrp8 is used to distinguish the yeast (S. cerevisiae) protein from the human form. sPrp8 SPP42 (Schmidt et al. 1999) or sPrp8 cwf6 (McDonald et al. 1999;Ohi et al. 2002) defines the ortholog in Schizosaccharomyces pombe. Confusingly, the cdc28 gene in S. pombe is also referred to as prp8 as a consequence of its role in both pre-mRNA splicing and cell cycle progression, and there is also a temperature-sensitive allele called prp8-1 that causes accumulation of pre-mRNA upon a shift to nonpermissive temperatures (Lundgren et al. 1996;Imamura et al. 1998). Cdc28 prp8 encodes a 112-kDa DEAH-box protein. This protein is not the ortholog of the U5 snRNP protein of S. cerevisiae that is discussed here.In discussions of pre-mRNA-protein cross-links or mutations that affect intron-exon junctions, 5ЈSS+2 refers to the second intronic base from the 5Ј end of the intron, 5ЈSS-2 is the penultimate base of the 5Ј exon, and 3ЈSS-2 is the penultimate base of the intron. PRE-mRNA SPLICINGPre-mRNA splicing involves two trans-esterification reactions within the highly dynamic spliceosome complex. A vast amount of mainly biochemical data led to a consensus view of an ordered pathway of spliceosome assembly that will be described in outline here (for further details, see Kramer 1996;Burge et al. 1999;Brow 2002). The small nuclear RNA-protein (snRNP) complexes, known as U1, U2, U4, U5, and U6 snRNPs, play key roles. U1 is the first snRNP to associate with pre-mRNA, interacting with the 5Ј splice site (5Ј...

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Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

Section: Mpn (Mpr-1 Pad-1 N-terminal) Domainmentioning

confidence: 99%

See 1 more Smart Citation

Prp8 protein: At the heart of the spliceosome

Grainger¹,

Beggs²

2005

RNA

316

386

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“…References; Dutch family (van Lith-Verhoeven, et al, 2002), British 1 (McKie, et al, 2001;, British 2 (described herein), South African (Greenberg, et al, 1994;McKie, et al, 2001), US1 (Walia, et al, 2008), Japanese (Kondo, et al, 2003), Spanish 1-4 (Martinez-Gimeno, et al, 2003), British 3, 4 and 5 (described herein) and US2 (Kojis, et al, 1996). frame-shift 2325fsX2359 (Kondo, et al, 2003) c.6991delG frame-shift E2331fsX2358 (Sullivan, et al, 2006) IVS exon 41/ 42 junction IVS41-4G>A Splice site change (Sullivan, et al, 2006) -Gimeno, et al, 2003) Nucleotide numbering reflects cDNA numbering with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence (accession number NG_009118), according to journal guidelines (www.hgvs.org/mutnomen). The initiation codon is codon 1.…”

Section: Genotype-phenotype Analysismentioning

confidence: 99%

“…It is highly conserved in both sequence and size, which varies between 220 and 280kDa in different organisms (Hodges, et al, 1995;Luo, et al, 1999). Sixteen different PRPF8 mutations, including missense, premature stop and deletions have been identified to date (De Erkenez AC, 2002;Kondo, et al, 2003;Martinez-Gimeno, et al, 2003;McKie, et al, 2001;Ziviello, et al, 2005), all but one of which cluster in a highly conserved region within the last exon. These mutations account for approximately 3% of dominant RP or around 1% of all RP cases (Sullivan, et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes

et al. 2010

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PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit.

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Phenotypic Expression of a PRPF8 Gene Mutation in a Large African American Family

Walia

Fishman²,

Zernant-Rajang³

et al. 2008

Arch Ophthalmol

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To describe the phenotype and determine the genetic cause of autosomal dominant retinitis pigmentosa (adRP) in a large African American family. Methods: Fourteen members from 4 generations were evaluated clinically. Visual field measurements were made for most, and electroretinography, Tü binger perimetry, and optical coherence tomographic testing were done for individual family members. Genetic screening was performed on a recently introduced adRP microarray that contains approximately 400 mutations from 13 genes. Results: All of the affected members had a type 1 form of adRP, characterized by early onset of symptoms for visual impairment, marked central and peripheral vision loss, nondetectable electroretinographic responses, and decreased macular thickness on optical coherence tomographic testing. Two variants in the PRPF8 gene were identified in the proband, H2309R and IVS41-4G→A. The H2309R mutation segregated with the disease in the family, whereas the IVS41-4G→A variant did not. Conclusions: The severe form of adRP was caused by the PRPF8 H2309R variant, whereas the IVS41-4G→A variant was benign. Clinical Relevance: PRPF8 mutations should be suspected in patients with a type 1 form of adRP. A combination of advanced clinical workup and comprehensive genetic testing is essential for the precise diagnosis of diseases with high genetic heterogeneity such as RP.

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Mutations in the Pre-mRNA Splicing-Factor GenesPRPF3,PRPF8, andPRPF31in Spanish Families with Autosomal Dominant Retinitis Pigmentosa

Cited by 81 publications

References 28 publications

Prp8 protein: At the heart of the spliceosome

Prp8 protein: At the heart of the spliceosome

Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes

Phenotypic Expression of a PRPF8 Gene Mutation in a Large African American Family

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