Human Molecular Genetics, 2001, Vol. 10, No. 15 1555-1562
© 2001 Oxford University Press
Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)
Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James’ University Hospital, Leeds LS9 7TF, UK, 1Section of Molecular Genetics, Division of Biomedical Sciences, Imperial College School of Medicine, London SW7 4AY, UK, 2Department of Human Genetics, University of Cape Town Medical School, Cape Town, South Africa, 3Department of Ophthalmology and 4Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands, 5CERA, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia and 6Department of Molecular Genetics, Institute of Ophthalmology, University College London, London EC1V 9EL, UK
Received March 30, 2001; Revised and Accepted May 25, 2001.
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ABSTRACT |
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Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The term retinitis pigmentosa (RP) was first used by Donders in 1857 to describe the pattern of pigmentation seen in the peripheral retina of a proportion of blind people. Patients with RP report narrowing of visual fields (tunnel vision) and night blindness, often progressing to complete blindness in later life. This condition affects approximately 1 in 4000 individuals and exhibits considerable genetic heterogeneity with 30 reported genes or loci at which mutations give rise to an RP phenotype. Eleven known autosomal dominant loci include five identified genes and a further six loci for which the genes remain to be found. This locus was first identified by linkage mapping in a large South African family of British ancestry (1). It was later confirmed with the identification of two further RP13 linked families, one from the US (2) and the other from the UK (3). The phenotype in the UK family is one of classical RP with relatively early onset and a severe prognosis in comparison with other dominant forms of RP. Affected individuals consistently report night blindness and visual field loss by 5 years of age and are usually registered blind or partially sighted by 30 years. Haplotype analysis in the South African family placed RP13 within a 3 cM interval between the markers D17S1529 and D17S831 (4), which distinguished the locus genetically from a number of other eye disease loci in the region (Fig. 1). Two further RP13 linked families have recently been identified, one from the UK (J.C. McHale, E.E. Tarttelin and C.F. Inglehearn, unpublished data) and the other from The Netherlands (5), bringing the total to five.
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RESULTS |
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We carried out further haplotype analysis on the South African, Dutch and the two UK families. This revealed that the two UK families are clearly related and are therefore in effect one extended pedigree, but that this larger UK pedigree, the South African and Dutch families are unrelated (Fig. 2). To further characterize the RP13 interval, a physical contig of the region was used to create an expression map of uniquely ordered expressed sequence tags (ESTs) and known genes (6). Sequence data from the Whitehead Institute chromosome 17 project (www.genome.wi.mit.edu/) was integrated with this data and used to orientate genetic markers. A new microsatellite marker designated 4kbGT was identified in the interval, and this further refined the distal boundary by detecting crossovers in the UK and South African families (Figs 1 and 2). The proximal boundary remained defined by the marker D17S831 which detected a crossover in the South African family (4). Within the D17S831-4kbGT interval, we identified the known genes PEDF, RPA1, PLI, PITPn-a, SKIP, KIAA00149, MYO1-ß and IMPC23B, a retinal EST AA0016967 and several putative genes predicted by the nucleotide identification package NIX (www.hgmp.mrc.ac.uk). We obtained the IMAGE cDNA clone from which EST AA016967 was derived and sequenced this in its entirety. This revealed a small region of unique sequence at one end of the clone, but the remainder consisted of Alu repeat and it therefore seems likely that this clone represents a cloning artefact. Nevertheless, this stretch of repeat-free sequence and each of the other candidate genes listed above were excluded from involvement in RP13 by mutation screening in affected members of the UK and South African families by single strand conformation polymorphism (SSCP) and genomic sequencing of all exons including splice donor/acceptor boundaries.
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Spectrum of mutations in the PRPC8 gene
We then examined the gene encoding the 220 kDa U5 snRNP factor denoted PRP8. The genomic structure of the human PRPC8 gene was ascertained on the basis of comparisons between the cDNA (GenBank accession no. AB007510) (7) and genomic bacterial artificial chromosome (BAC) sequences from the chromosome 17 sequencing project (BAC RP11-145P4, GenBank accession no. AC002093; and BAC RP11-433M14, accession no. AC068936). This showed that this large 2335 amino acid protein was encoded by 42 exons spanning
36 kb of genomic sequence (Fig. 1). All of the exons were screened by SSCP and genomic sequencing in DNA samples from affected members of the three RP13 linked families. Three different missense mutations were found within two adjacent codons in the last exon of the PRPC8 gene, one in each family (Fig. 3A), and in each case they segregated perfectly with the disease. The UK and South African families have different base changes at the same nucleotide position (nucleotide 6967; Table 1) with a third missense mutation in affected individuals from the Dutch pedigree identified in the adjacent codon (nucleotide 6970). Segregation of the nucleotide 6967 mutations in the complete South African and UK pedigrees was demonstrated by virtue of loss of an ApaL1 restriction cleavage site on the mutated allele (Fig. 3B). Segregation of the Dutch mutation can be detected as loss of HaeIII or DraII restriction sites (data not shown).
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C resulting in H2309P amino acid change in the UK family, (3) mutation c.6967A
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Further screening using these restriction digestion assays on a collection of 332 RP patient DNAs from centres in the UK and Australia revealed no further cases with these specific mutations. However, a preliminary mutation screen of all 42 PRPC8 exons by SSCP in a sample of 60 autosomal dominant RP (adRP) cases from the UK identified four further missense mutations in exon 42 (Fig. 3C and Table 1). One of these exhibited a change at the preceding base to the Dutch mutation (nucleotide 6969) within the same codon (2310). Another had a base change at nucleotide 6953 which cosegregated with RP in two affected relatives of the patient. The third and fourth mutations were each in single patients and altered bases at positions 6942 (codon 2301) and 6983 (codon 2314). All seven mutations are in a 42 bp sequence (14 codons)
100 bp from the stop codon at the 3' end of this large transcript. The ApaL1 and HaeIII restriction assays were also used to exclude the occurrence of the sequence changes seen in the RP13 linked families in 120 normal control DNA samples, ruling out the possibility that they are neutral sequence variations occurring with a significant frequency in the general population. Similarly, an SSCP screen of PRPC8 exon 42 in 572 control chromosomes from individuals of a similar ethnic background revealed no sequence changes, confirming that the mutations are unlikely to be common polymorphisms.
PRPC8 gene expression is ubiquitous
The EST database (www.ncbi.nlm.nih.gov/UniGene/) reveals that PRPC8 is expressed in a wide range of tissues. However, of approximately 450 EST entries, over 70 are derived from neural tissue, of which 18 are from the eye. Northern blot analysis using a probe from the 3' end of the PRPC8 gene, which included exon 42, gave a single band of 7 kb in total RNA from six tissues. RT–PCR was carried out on total RNA from a variety of normal tissue sources including retina and other neuronal tissues. Multiplexed RT–PCR was carried out with primers within exons 41 and 42 of PRPC8 as a single amplicon to ensure that exon 42 is present in retinal transcripts (Fig. 4). The PRPC8 amplicon is clearly expressed in all the tissues as a single band of 124 bp. Control primers for the GAPDH gene amplified a 220 bp fragment in each lane.
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Sequence conservation
Protein alignment at exon 42 between human PRP8 and its orthologues in other species was carried out using the programme Clustal, and the shaded boxes were created using the programme Mac-Boxshade (Fig. 5). The parameters employed by the shading process are not confined only to amino acid sequence but also take account of conservation of the amino acid physiochemical properties. This analysis illustrates conservation of the two amino acids changed in the three RP13 linked families and one non-related adRP case (codons 2309 and 2310) in Drosophila melanogaster, Arabidopsis thaliana, Caenorhabditis elegans, Schizosaccharomyces pombe and Trypanosoma bruceii. Particularly striking is the level of homology around residues 2309 and 2310 and the absolute conservation of these two residues throughout the species shown in the multiple alignment. Additionally, the proline residue at position 2301 has the same high degree of conservation and is altered in one adRP case. The remaining missense mutations alter the amino acid residues 2304 and 2314, which are also conserved but to a lesser degree.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Prp8 is the most highly conserved large nuclear protein known to date (8), yet the amino acid sequence shows no evidence of homology to any recognized protein domains other than its orthologues in other species. Functional information has been derived from studies in the budding yeast Saccharomyces cerevisiae, which identified some of the protein components necessary for spliceosome formation. Over 40 precursor mRNA processing (prp) proteins have been identified in yeast to date, of which Prp3, Prp4, Prp5, Prp7, Prp8 and Prp11 have been shown to be vital for spliceosome assembly in vitro (9). Yeast Prp8 protein is thought to be the core component of the U5 snRNP and is required for formation of the U4/U6-U5 tri-snRNP, without which spliceosome assembly and pre-mRNA processing do not take place (10). The U1 snRNP is the first particle to interact with the substrate mRNA precursor, followed by U2 snRNP. Concurrently, the U4/U6 and U5 snRNPs associate to form the triple snRNP and this then joins the U1/U2-pre-mRNA complex to form the spliceosome (11). UV-crosslinking studies have shown that Prp8 interacts with the pre-mRNA substrate at both the 5' and 3' splice sites, and may function as the principle anchoring factor for exons in the spliceosome (12–15). A region of the Prp8 protein near the C-terminus has been shown to crosslink with the 5' splice-site consensus sequence (16). This is
400 amino acid residues away from the region containing the mutations described above, but the relationship between them in the tertiary structure is unknown. The study of a cold-sensitive yeast mutant has led to the proposal that Prp8 may also facilitate unwinding of the U4 and U6 snRNAs during activation of the spliceosome to the catalytic ‘complex C’ (17–18). Therefore, because of its dynamic interactions as part of the spliceosome and the many interactions it has with other splicing factors, Prp8 may represent the spliceosomal protein with the most complex structural organization, providing important catalytic and regulatory functions for pre-mRNA processing. Having such a central role in this basic housekeeping function, PRPC8 was therefore not an obvious candidate for involvement in retinal disease. Most of the genes implicated in retinal disease have retina-specific expression and, where function is known, encode proteins essential for photoreceptor development/structure or are components of either the phototransduction cascade or the visual cycle which provides and recycles 11-cis-retinaldehyde (19). This may, however, represent a bias in the selection of candidate genes when screening in these diseases, and a number of retinal disease genes identified more recently have ubiquitous expression patterns. These include the RPGR and RP2 genes mutated in X-linked RP, the EFEMP1 gene involved in dominant drusen, the MERTK gene involved in recessive RP, the OPA1 gene involved in optic atrophy and the TIMP3 gene mutated in Sorsby’s macular dystrophy (www.sph.uth.tmc.edu/retnet). The RPGR gene encodes a protein with homology to the guanine-nucleotide-exchange factor RCC1, and alternatively spliced products specific to retina have been identified in the 3' half of the gene that harbours most of the mutations in RP3 kindreds (20). RT–PCR analysis of the 3' exons of the PRPC8 gene has not provided any evidence of alternatively spliced transcripts in retina or in any other tissue thus far examined. Exon 42 is ubiquitously expressed in the 10 tissue types examined and we observed no discernible differences in expression levels, though reports of such differences in expression have been found in the literature, with the highest expression being observed in muscle tissue (21).
Nevertheless, we have found different mutations in three RP13 linked families and four further mutations in patients with a family history of dominant RP. This provides compelling evidence that PRPC8 is indeed the gene mutated in this form of dominant RP. The occurrence of seven missense mutations within the last of 42 exons in this large gene may imply that this region of the protein is involved in some particular aspect of retinal maintenance or function. The fact the mutations are all missense, and that the RP13 locus is associated with a relatively severe phenotype, may imply a dominant negative mechanism for disease causation. Nonsense mutations in genes such as Rds/peripherin (22) and RP1 (23) generally correspond to a milder phenotype which may represent a haploinsufficiency defect.
Most of the current knowledge about Prp8 function derives from studies in yeast, whereas Prp8 function in higher eukaryotes is less well researched. It is therefore possible that this discovery will shed light on some other unknown function attributable to Prp8 which is specific to the retina. Prp8 and some of the other protein factors known to interact in spliceosome assembly are also thought to be involved in cell cycle control (24,25), carbon catabolism (26), cytoplasmic mRNP export and processing (27), protein secretion and Golgi trafficking (28) as well as possibly DNA repair (29). Alternatively, it may be that Prp8 and other ubiquitously expressed genes mutated in retinal disease represent a series of rate-limiting steps in what is one of the fastest metabolizing tissues in the human body (30). Thus, a defect in splicing or mitochondrial metabolism which is sub-pathological in other tissues might manifest as a disease only in the retina.
On the other hand, the involvement of factors specifically associated with splicing in neuronal degeneration is not unprecedented. SMN1, the gene mutated in spinal muscular atrophy (SMA) types 1, 2 and 3, is thought to play a role in both snRNP assembly in the cytoplasm and regeneration in the nucleus by binding to and aggregating the U1, U2, U4 and U5 snRNP-specific Sm proteins (31). The basis for the absolute specificity of motor neuron death in SMA remains unclear, since this protein, like Prp8, is expressed in a number of tissues, including other regions of the brain not affected in SMA. Aetiological parallels can therefore be drawn between SMA and RP13, which both involve mutations in ubiquitously expressed splicing factors leading to neuronal degeneration.
In mammals, the vast majority of introns are removed by the major U2-dependent spliceosome complex (composed of four snRNPs; U1, U2, U4/U6 and U5). A second type of spliceosome was recently discovered—the U12-dependent spliceosome complex that removes so-called U12-dependent introns (32). The U12-dependent introns comprise <1% of all introns. Interestingly, the splicing mechanism of this class of introns not only recognizes different splice donor and acceptor consensus sequences, but employs a different set of snRNPs. The exception to this is the U5 complex which appears to have a pivotal role in both these systems. One family of genes which maintain U12-dependent introns is the voltage-gated sodium and calcium channel 
-subunits (33). Mutations in these genes cause numerous neuromuscular and neurological diseases (34). One could therefore postulate that the exon 42 mutations in PRPC8 mediate their effect through a failure of the U12-dependent spliceosome complex. Significantly, the U12-dependent splicing mechanism is absent from budding yeast which has been the main experimental organism furnishing most of the current knowledge of Prp8 function.
In conclusion, we have shown that mutations in PRPC8, the human orthologue of the yeast splicing factor Prp8, are implicated in the RP13 form of RP. As the function of this protein in humans is less well studied than in yeast, it is possible that this observation will highlight some as yet unknown function for Prp8 outside its core role in mediating spliceosome assembly and catalysis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients’ sample collection
Patients and first degree relatives were recruited, with informed consent and local ethics committee approval, through ophthalmic clinics in London, The Netherlands, South Africa and Australia. Genomic DNA was prepared from peripheral blood leucocytes by standard protocols. Samples from each of the families described herein were subjected to linkage analysis and were shown to link to the RP13 locus for dominant RP on chromosome 17p13.3 (1,3,5).
Identification of 17p13.3 ESTs and sequence-tagged sites (STSs)
EST and gene sequences were identified as mapping in or near the RP13 interval from our own physical mapping data (6), and from the GeneMap (www.ncbi.nlm.nih.gov/genemap/), UniGene (www.ncbi.nlm.nih.gov/UniGene/), Whitehead Institute (www.genome.wi.mit.edu/) and Wiezmann Institute (www.bioinformatics.weizmann.ac.il/) databases. Gene-specific STSs and primers for individual exons were purchased from Life Technologies.
P1-derived artificial chromosome (PAC) analysis and sequence sampling
PAC clone DNA was isolated using the alkaline lysis method (24). PAC-end sequence derivation was accomplished with standard T7- and Sp6-specific primers using the [33P]-dideoxy terminator kit (Amersham-Pharmacia Biotech). In addition, further sequence of YAC/PAC clones was determined by vectorette PCR (36). Finally, in an attempt to identify new genetic markers in the RP13 region, PAC 222-B19 DNA was digested with HindIII, size-fractionated by agarose gel electrophoresis and Southern blotted. A d(GT)10 oligomer was then used to probe the filter, identifying a 4 kb fragment containing the d(GT)15 repeat, referred to as 4kbGT. This was used to refine the distal crossover boundary in the UK and South African families.
Mutation screening
Coding exons were amplified from patient DNA using primers in flanking intron and untranslated region sequences (for exon 42; forward primer, 5'-CCAGCATCTTGCTGTGAACCGC-3' and reverse primer, 5'-TGCATGAGGCAGGAGCCCTGTT-3'). PCR amplification was carried out in 20 µl reaction volumes containing 10 mM Tris–HCl, pH 8.9, 50 mM KCl, 1.5–2.5 mM MgCl2, 0.1% Triton X-100, 10 pmol of each primer, 200 µM each dNTP, 50–100 ng of patient genomic DNA and 0.25 U of either BiotaqTM thermostable DNA polymerase (Bioline) or Red-HOT DNA Polymerase (ABgene). Cycling parameters were 3 min at 94°C, followed by 35 cycles of 20 s at 94°C, 20 s at 58°C and 30–90 s at 72°C, with a final 10 min extension at 72°C. The PCR products were purified using a pre-sequencing exonuclease and phosphatase digestion kit (Amersham-Pharmacia Biotech). Alternatively, PCR products were purified by ultracentrifugation through Qiaquick columns (Qiagen). Sequences were size-fractionated on standard 6% acrylamide denaturing gels using ready-made sequegel-6 mix (National Diagnostics) and Sequi-Gen II apparatus (Bio-Rad). Sequences were aligned using the Autoassembler software from Applied Biosystems. SSCP analysis was carried out by incorporating [33P]dCTP (0.02 µCi per sample) and size fractionating the samples on 6% non-denaturing polyacrylamide gels (acrylamide monomer:Bis acrylamide ratio of 49:1) for 20 h at room temperature in 0.5x TBE supplemented with 5% glycerol. Gels were then dried and exposed to autoradiography for 24–72 h.
Segregation analysis by ApaL1 restriction digestion
Segregation of mutations in the UK and South African RP13 linked families was tested by digestion of the exon 42 PCR fragment generated by primers detailed above with the restriction enzyme ApaL1. In each case, 6 ml of a 30 ml PCR reaction was incubated with 10 U of ApaL1 in a 30 ml reaction volume at 37°C for 3 h. The products were then analysed by electrophoresis on a 3.0% NuSieve gel (FMC) at 10 V/cm.
RT–PCR
Human kidney, heart, lung, liver, placenta, adult brain, fetal brain, spinal cord and cerebellum total RNA were purchased from either Clontech or Ambion. Retinal RNA was isolated from human retina obtained from the Eye Bank in Bristol, UK. Random priming and reverse transcription was carried out using Superscript AMV reverse transcriptase from Life Technologies, according to the manufacturer’s recommendations. Primer pairs were designed to amplify a fragment containing exons 41 and 42 of the PRPC8 gene, spanning intron 41 [exon 42 (RT) forward, 5'-AGTTGAGGAAGTGAGAGGCCTGT-3' and exon 41 (RT) reverse, 5'-CCAGTCCTCGTGGAACTACAACTTC-3']. The PCR products were then separated by agarose gel electrophoresis on 3.0% Nu Sieve (FMC) agarose gels.
Northern blot analysis
Total RNA (5 µg) from kidney, lung, heart, liver, brain and retina were analysed by electrophoresis on a 1% formaldehyde gel and blotted to Hybond N+ positively charged nylon membrane (Amersham-Pharmacia Biotech). The filter was hybridized in Perfecthyb plus (Sigma) following the product information supplied, with a probe covering exons 41 and 42 of PRPC8 which had been labelled by the rediprime II random labelling kit (Amersham-Pharmacia Biotech).
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ACKNOWLEDGEMENTS |
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We thank the families for their participation in this research and also Catherine Plant, Lin Mulhall, Melinda Cain, Lecia Bartman and Hendrik P.M. Brink for help in ascertaining patients. This work is funded by the The Wellcome Trust (grant no. 035535), the British Retinitis Pigmentosa Society, The Retinal Preservation Foundation of South Africa, The Foundation Fighting Blindness, USA, (R.S.R and J.G), The British Council/National Research Foundation of South Africa, (C.F.I and R.S.R). The Stichting Researchfonds Oogheelkunde, The Stichting Ondersteuning Oogheelkunde’s-Gravenhage and the Stichting Blindenhulp.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 113 206 5698; Fax: +44 113 244 4475; Email: cinglehe@hgmp.mrc.ac.ukThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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REFERENCES |
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