Mutations in PRPF31 Inhibit Pre-mRNA Splicing of Rhodopsin Gene and Cause Apoptosis of Retinal Cells

Lu, Yuan; Kawada, Mariko; Havlioglu, Necat; Tang, Hao; Wu, Jane Y.

doi:10.1523/jneurosci.2399-04.2005

Cited by 64 publications

(58 citation statements)

References 44 publications

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“…It should be pointed out that it remains possible that photoreceptors from different species may have different properties and sensitivities to the presence of mutant Prp31 gene products. Differences in processing of pre-mRNA transcripts have been observed in three separate studies on the rodopsin transcript (Deery et al, 2002;Yuan et al, 2005;Wilkie et al, 2008). The first study reported no effects on the splicing of bovine rodopsin transcripts in the presence of the Prp31 mutant protein in an in vivo splicing assay whereas the latter studies demonstrated dominant effects of Prp31 mutations in affecting splicing efficiency of human rodopsin transcript.…”

Section: Discussionmentioning

confidence: 94%

“…overexpression of hAD5 mutant form of human Prp31 gene in cultured cells leads to neuronal death and reduced splicing efficiency of a subset of retinal genes (Yuan et al, 2005;Mordes et al, 2007). In our current study, simply expressing hAD5 Prp31 mutant in Drosophila eye did not lead to detectable effect on photoreceptor cells.…”

Section: Discussionmentioning

confidence: 99%

“…The AD5 mutation is caused by an 11bp deletion (Vithana et al, 2001), leading to formation of a truncated protein product of 371 amino acids. Using a minigene-cotransfection method in HEK cells, our previous studies show that the AD5 mutation significantly inhibits splicing of a subset of retina-specific transcripts (Yuan et al, 2005;Mordes et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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The splicing factor Prp31 is essential for photoreceptor development in Drosophila

Ray¹,

Luo²,

Rao³

et al. 2010

Protein Cell

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Retinitis pigmentosa is a leading cause of blindness and a progressive retinal disorder, affecting millions of people worldwide. This disease is characterized by photoreceptor degeneration, eventually leading to complete blindness. Autosomal dominant (adRP) has been associated with mutations in at least four ubiquitously expressed genes encoding pre-mRNA splicing factorsPrp3, Prp8, Prp31 and PAP1. Biological function of adRPassociated splicing factor genes and molecular mechanisms by which mutations in these genes cause cell-type specific photoreceptor degeneration in humans remain to be elucidated. To investigate the in vivo function of these adRP-associated splicing factor genes, we examined Drosophila in which expression of fly Prp31 homolog was down-regulated. Sequence analyses show that CG6876 is the likely candidate of Drosophila melanogaster Prp31 homolog (DmPrp31). Predicted peptide sequence for CG6876 shows 57% similarity to the Homo sapiens Prp31 protein (HsPrp31). Reduction of the endogenous Prp31 by RNAi-mediated knockdown specifically in the eye leads to reduction of eye size or complete absence of eyes with remarkable features of photoreceptor degeneration and recapitulates the bimodal expressivity of human Prp31 mutations in adRP patients. Such transgenic DmPrp31RNAi flies provide a useful tool for identifying genetic modifiers or interacting genes for Prp31. Expression of the human Prp31 in these animals leads to a partial rescue of the eye phenotype. Our results indicate that the Drosophila CG6876 is the fly ortholog of mammalian Prp31 gene.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The splicing factor Prp31 is essential for photoreceptor development in Drosophila

Ray¹,

Luo²,

Rao³

et al. 2010

Protein Cell

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“…Studies first supported possible explanation 2 and suggested that the removal of intron 3 of RHO is inhibited by the mutated splice factor PRPF31 (Yuan et al, 2005).…”

Section: Retinitis Pigmentosa and Progressive Rod Cone Diseasesmentioning

confidence: 99%

“…(3) Due to specialized requirements (e.g. transcript turnover), photoreceptors depend more strongly than other cell types on efficient splicing.Studies first supported possible explanation 2 and suggested that the removal of intron 3 of RHO is inhibited by the mutated splice factor PRPF31 (Yuan et al, 2005).The authors expressed the mutated PRPF31 to detect the splice defect in RHO.Subsequently, studies suggested that haploinsufficiency is the underlying mechanism for PRPF31 mutations, i.e. the mutated allele is not expressed and the reduced gene The molecular basis of human retinal and vitreoretinal diseases properties of a single RP gene.…”

mentioning

confidence: 99%

The molecular basis of human retinal and vitreoretinal diseases

Berger¹,

Kloeckener-Gruissem²,

Neidhardt³

2010

Progress in Retinal and Eye Research

503

443

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The molecular basis of human retinal and vitreoretinal diseases pathologies of other tissues (syndromic forms) or only affects the retina, retinal pigment epithelium and the vireous body (non-syndromic forms). In addition, the mode of inheritance was used as one characteristic feature of the different disease phenotypes in order to categorize them. Our aim was to provide a comprehensive overview about the molecular basis of retinal and vitreoretinal diseases and to discuss selected aspects in more detail. Non-syndromic retinal and vitreoretinal diseases Diseases of rod photoreceptor cells (stationary and progressive)Rod photoreceptors represent the vast majority of light sensitive cells in the human retina. There are approximately 20 times more rods than cones. These cells are spezialized for low light intensities and are responsible for visual perception under dim light conditions. The center of the human retina, which contains the macula and fovea centralis, is devoid of rod photoreceptor cells but the flanking areas have the highest rod content, which decreases almost lineary towards the retinal periphery.The two major classes of stationary and progressive retinal diseases in humans arerepresented by different forms of stationary night blindness and retinitis pigmentosa, respectively. Congenital stationary night blindness / stationary rod diseasesAs the name implies, congenital stationary night blindness (CSNB) is a nonprogressive visual impairment present at birth. However, it is also one of the first symptoms in progressive diseases, including retinitis pigmentosa (RP). Therefore, a differential diagnosis by genetic testing can provide helpful and important information to the affected individuals and families, in order to exclude or confirm the clinical diagnosis and to provide counselling. Bech-Hansen et al., 1998; Bech-Hansen et al., 2000;Dryja et al., 1993; Dryja et al., 1996; Dryja et al., 2005; Fuchs et al., 1995;Gal et al., 1994;Li et al., 2009; Pusch et al., 2000;Strom et al., 1998;Wycisk et al., 2006;Yamamoto et al., 1997;Zeitz et al., 2005;Zeitz et al., 2006 inheritance. The disease was found to be due to mutations in the alpha subunit of transducin (Dryja et al., 1996). The Schubert Bornschein disease can be subdivided in (i) CSNB1 or complete CSNB and (ii) CSNB2 or incomplete CSNB. In CSNB1, the rod b-wave is significantly reduced or absent, while that of the cones is largely Retinitis pigmentosa and progressive rod cone diseasesThe term retinitis pigmentosa (RP) describes a group of clinically similar phenotypes associated with genetically heterogeneous causes. The disease onset and progression may vary significantly among patients, even within the same family. The patients frequently experience night blindness in the early phase of the disease, The molecular basis of human retinal and vitreoretinal diseases Collin et al., 2008; den Hollander et al., 1999; Dryja et al., 1995; Gal et al., 2000; Huang et al., 1995; Martinez-Mir et al., 1998;Maw et al., 1997;Maw et al., 2000;McLaughlin et a...

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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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Mutations in PRPF31 Inhibit Pre-mRNA Splicing of Rhodopsin Gene and Cause Apoptosis of Retinal Cells

Cited by 64 publications

References 44 publications

The splicing factor Prp31 is essential for photoreceptor development in Drosophila

The splicing factor Prp31 is essential for photoreceptor development in Drosophila

The molecular basis of human retinal and vitreoretinal diseases

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

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