Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa

Keen, T J; Hims, MM; McKie, AB; Moore, AT; Doran, RM; Mackey, DA; Mansfield, DC; Rf, Mueller; Bhattacharya, SS; Bird, AC; Af, Markham; Inglehearn, C. F.

doi:10.1038/sj.ejhg.5200797

Cited by 80 publications

(39 citation statements)

References 17 publications

(18 reference statements)

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“…The latter situation is the case for the four RP genes that encode mRNA splicing factors, namely RP9 (PAP1), RP11 (PRPF31), RP13 (PRPC8), and RP18 (HPRP3) (MIM]s 607331,606419,607300,and 607301,respectively). Dominant mutations in these four ubiquitously expressed genes cause forms of RP (MIM]s 180104, 600138, 600059, and 601414, respectively) [Vithana et al, 2001;McKie et al, 2001;Chakarova et al, 2002;Keen et al, 2002]. They all encode components of the spliceosome, a macromolecular complex composed of proteins and RNA molecules whose major function is to splice introns out of RNA transcripts [Zhou et al, 2002;Maita et al, 2004Maita et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Variation in retinitis pigmentosa-11 (PRPF31orRP11) gene expression between symptomatic and asymptomatic patients with dominantRP11mutations

et al. 2006

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Dominant mutations in the mRNA splicing factor gene PRPF31 (RP11) cause retinitis pigmentosa with reduced penetrance. We studied the expression of RP11 in lymphoblast cell lines from 10 patients, including three who were clinically asymptomatic, with six distinct RP11 mutations. Five of the six mutations were characterized and all five created premature nonsense codons or eliminated the normal initiation codon. Semiquantitative RT-PCR indicated that an average of only 17% of the RP11 mRNA was derived from the mutant allele, likely because the mutant mRNA transcripts were degraded by nonsense-mediated decay. Gene expression levels were measured by Affymetrix and CodeLink microarrays and, for RP11 transcripts, also by real-time PCR. Combined wild-type-plus-mutant RP11 mRNA expression from symptomatic patients was 52 to 77% of that in controls (p < or = 0.0005). Clinically asymptomatic carriers had levels of RP11 mRNA similar to controls and 29-42% higher than in clinically affected patients (0.0001

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Section: Introductionmentioning

confidence: 99%

Variation in retinitis pigmentosa-11 (PRPF31orRP11) gene expression between symptomatic and asymptomatic patients with dominantRP11mutations

et al. 2006

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“…Nonetheless, it can be responsible for a disease that is restricted to the retina only, because heterozygous patients carrying PRPF31 mutations suffer from RP with no associated syndromes (8,9). The role of PRPF31 in the etiology of dominant RP is very likely linked to its main function in the mRNA splicing process, because 4 other essential pre-mRNA splicing factors and key components of the spliceosome have also been found to be involved in this disease (10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

Frio¹,

Wade²,

Ransijn³

et al. 2008

J. Clin. Invest.

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Dominant mutations in the gene encoding the mRNA splicing factor PRPF31 cause retinitis pigmentosa, a hereditary form of retinal degeneration. Most of these mutations are characterized by DNA changes that lead to premature termination codons. We investigated 6 different PRPF31 mutations, represented by single-base substitutions or microdeletions, in cell lines derived from 9 patients with dominant retinitis pigmentosa. Five of these mutations lead to premature termination codons, and 1 leads to the skipping of exon 2. Allele-specific measurement of PRPF31 transcripts revealed a strong reduction in the expression of mutant alleles. As a consequence, total PRPF31 protein abundance was decreased, and no truncated proteins were detected. Subnuclear localization of the full-length PRPF31 that was present remained unaffected. Blocking nonsense-mediated mRNA decay significantly restored the amount of mutant PRPF31 mRNA but did not restore the synthesis of mutant proteins, even in conjunction with inhibitors of protein degradation pathways. Our results indicate that most PRPF31 mutations ultimately result in null alleles through the activation of surveillance mechanisms that inactivate mutant mRNA and, possibly, proteins. Furthermore, these data provide compelling evidence that the pathogenic effect of PRPF31 mutations is likely due to haploinsufficiency rather than to gain of function.

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“…A colocalized, nonprocessed pseudogene was also identified for the RP9 gene (EntrezGeneID: 6100; RefSeq: NM_203288.1; MIM] 607331). A c.509A4G mutation (p.Asp170Gly) in this pseudogene (UI pseudogene ]11568 from NCBI Build 35) has been found to be associated with the RP9 form of adRP when present in the progenitor gene [Keen et al, 2002] [Bowne et al, 2002]. UI pseudogene ]13785 (NCBI Build 35) was predicted from the PGK1 gene and contains a c.837T4C mutation (p.Ile252Thr) associated with a PGK deficiency [Sugie et al, 1998].…”

Section: Computational Identi¢cation Of Pseudogenesmentioning

confidence: 99%

Genome-wide identification of pseudogenes capable of disease-causing gene conversion

et al. 2006

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Pseudogenes are remnants of gene duplication (nonprocessed pseudogenes) and retrotransposition (processed pseudogenes) events. This study describes methods for identifying gene conversion candidates from predicted pseudogenes. Pseudogenes may accumulate and harbor sequence variations over time that become disease-causing mutations when transferred to genes by gene conversion. A total of 14,476 pseudogenes were identified, including 3,426 nonprocessed pseudogenes. In addition, 1,945 nonprocessed pseudogenes that are localized near their progenitor gene were evaluated for their possible role in gene conversion and disease. All 11 known, human cases of gene conversion (with deleterious effects) involving pseudogenes were successfully identified by these methods. Among the pseudogenes identified is a retinitis pigmentosa 9 (RP9) pseudogene that carries a c.509A>G mutation which produces a p.Asp170Gly substitution that is associated with the RP9 form of autosomal dominant retinitis pigmentosa (adRP). The c.509A>G mutation in RP9 is a previously unrecognized example of gene conversion between the progenitor gene and its pseudogene. Notably, two processed pseudogenes also contain mutations associated with diseases. An inosine monophosphate dehydrogenase 1 (IMPDH1) pseudogene carries a c.676G>A mutation that produces a p.Asp226Asn substitution that causes the retinitis pigmentosa 10 (RP10) form of adRP; and a phosphoglycerate kinase 1 (PGK1) pseudogene (PGK1P1) carries a c.837T>C mutation that produces a p.Ile252Thr substitution that is associated with a phosphoglycerate kinase deficiency. Ranking of nonprocessed pseudogenes as candidates for gene conversion was also performed based on the sequence characteristics of published cases of pseudogene-mediated gene conversion. All results and tools produced by this study are available for download at: http://genome.uiowa.edu/pseudogenes.

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Mutations in a protein target of the Pim-1 kinase associated with the RP9 form of autosomal dominant retinitis pigmentosa

Cited by 80 publications

References 17 publications

Variation in retinitis pigmentosa-11 (PRPF31orRP11) gene expression between symptomatic and asymptomatic patients with dominantRP11mutations

Variation in retinitis pigmentosa-11 (PRPF31orRP11) gene expression between symptomatic and asymptomatic patients with dominantRP11mutations

Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

Genome-wide identification of pseudogenes capable of disease-causing gene conversion

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