Expression of<i>PRPF31</i>mRNA in Patients with Autosomal Dominant Retinitis Pigmentosa: A Molecular Clue for Incomplete Penetrance?

Vithana, Eranga N.; Abu-Safieh, Leen; Pelosini, Lucia; Winchester, E.; Hornan, Dan; Bird, Alan C.; Hunt, David M.; Bustin, Stephen A.; Bhattacharya, Siladitya

doi:10.1167/iovs.03-0253

Cited by 116 publications

(110 citation statements)

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“…Rivolta et al studied the effect of five mutations on the expression levels of the PRPF31 gene, and found that asymptomatic carriers had PRPF31 mRNA levels similar to normal control individuals [10]. A similar finding was also made in lymphoblasts from a large RP11 family with an 11-bp deletion in exon 11 [16]. Together, these results may provide an important clue to understanding of the molecular mechanism explaining the phenotypic variability among RP11 patients.…”

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confidence: 79%

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

Liu

Dai

Jiqun

et al. 2008

Biochemical and Biophysical Research Communications

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A six-generation Chinese family with autosomal dominant retinitis pigmentosa (adRP) was identified and characterized. Genome-wide linkage analysis linked the family to markers D19S601 to D19S605, which span the PRPF31 gene on chromosome 19q13.33-13.43 (RP11) (LOD = 5.03). Direct DNA sequence analysis identified a novel splicing mutation (IVS1 +1 G > T) in affected family members, but not in unaffected family members and 200 normal controls. The splicing mutation occurs at the splicing donor of intron 1. Real time PCR with lymphoblastoid RNA samples from family members showed that in comparison to normal family members, the splicing mutation reduced the expression level of the PRPF31 mRNA by 57% in symptomatic patients and by 28% in clinically asymptomatic carriers. Our studies identify a novel splicing mutation in PRPF31 associated with adRP and suggest that the penetrance of RP11 mutations may be correlated with the expression level of the PRPF31 mRNA. KeywordsAutosomal dominant retinitis pigmentosa; PRPF31; Splicing mutation; Genetics; Linkage Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina, night blindness, constriction of visual field, and eventual loss of visual acuity. It is one of the leading causes of blindness in adults. Other typical features of RP include bone spicule-like retinal pigmentary deposits and reduced amplitudes or absent electroretinographic responses [1]. RP is the most frequent form of inherited retinopathies and has an incidence of 1 in 3,500 individuals worldwide [2,3]. The incidence is about 1 in 1,000 *Correspondence authors. E-mail address: E-mail: qkwang@mail.hust.edu.cn or E-mail: wangq2@ccf.org (Q.K. Wang); E-mail: lium@mail.hust.edu.cn (M. Liu). Fax: + 86 27 87794549. f Jingyu Liu and Xiaohua Dai contributed equally to this work Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The splicing of pre-mRNA in the nucleus is catalyzed by a large ribonucleoprotein complex (spliceosome). The splicesome is composed of the pre-mRNA substrate, small nuclear ribonucleoproteins (snRNPs) U1, U2, U4, U5 and U6, and other splicing factors. The PRPF31 is an integral component of the U4/U6+U5 tri-snRNP. It is thought to be responsible for tethering the tri-snRNP to the splicesome rather than forming or maintaining individual snRNP complexes [6][7][8]. Over 20 different mutations in the PRPF31 gene have been reported to be associated with adRP. The mutations identified to date include missense mutations, deletions, insertions and splicing mutations [2,3,[9][10][11][1...

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confidence: 79%

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

Liu

Dai

Jiqun

et al. 2008

Biochemical and Biophysical Research Communications

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“…The molecular mechanisms underlying this incomplete penetrance of Prp31 mutations in patients remain to be investigated. Possible explanations include differential expression of the wild type allele among different carriers or asymptomatic patients (Vithana et al, 2003) or the presence of a modifier gene (Rio Frio et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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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“…Many PRPF31 pathogenic alleles are null mutations, which have been previously shown to cause RP by haploinsufficiency, mainly through the NMD surveillance mechanism. 10,13,14 The variation in the levels of expression of the remaining wild-type allele directly correlates with incomplete penetrance in pedigrees. 11 Moreover, this expression variation has been shown to be a highly heritable character, depending on at least two transacting expression quantitative trait loci (eQTLs) (expression quantitative trait locus), which would therefore act as genetic modifiers.…”

Section: Discussionmentioning

confidence: 99%

“…Two of the adRP families had a large number of affected and nonaffected members available for analysis (families A6 and E4, Figure 1), whereas the size of the other two was much smaller (families A8 and A9, Figure 1), with merely 2-3 affected live members. Incomplete penetrance is relatively frequent in dominantly inherited disorders, such as adRP, 10,11 and thus, it was also taken into account while carrying out the co-segregation analysis. Also in our families there were some obligate carriers, who were non-penetrant but had affected progeny.…”

Section: Genotyping Of Autosomal Dominant Retinitis Pigmentosa Familiesmentioning

confidence: 99%

Comprehensive SNP-chip for retinitis pigmentosa-Leber congenital amaurosis diagnosis: new mutations and detection of mutational founder effects

et al. 2009

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Fast and efficient high-throughput techniques are essential for the molecular diagnosis of highly heterogeneous hereditary diseases, such as retinitis pigmentosa (RP). We had previously approached RP genetic testing by devising a chip based on co-segregation analysis for the autosomal recessive forms. In this study, we aimed to design a diagnostic tool for all the known genes (40 up to now) responsible for the autosomal dominant and recessive RP and Leber congenital amaurosis (LCA). This new chip analyzes 240 single nucleotide polymorphisms (SNPs) (6 per gene) on a high-throughput genotyping platform (SNPlex, Applied Biosystems), and genetic diagnosis is based on the co-segregation analysis of SNP haplotypes in independent families. In a single genotyping step, the number of RP candidates to be screened for mutations is considerably reduced, and in the most informative families, all the candidates are ruled out at once. In a panel of RP Spanish pedigrees, the disease chip became a crucial tool for selecting those suitable for genome-wide RP gene search, and saved the burdensome direct mutational screening of every known RP gene. In a large adRP family, the chip allowed ruling out of all but the causative gene, and identification of an unreported null mutation (E181X) in PRPF31. Finally, on the basis of the conservation of the SNP haplotype linked to this pathogenic variant, we propose that the E181X mutation spread through a cohort of geographically isolated families by a founder effect.

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Expression ofPRPF31mRNA in Patients with Autosomal Dominant Retinitis Pigmentosa: A Molecular Clue for Incomplete Penetrance?

Cited by 116 publications

References 18 publications

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

Identification and functional characterization of a novel splicing mutation in RP gene PRPF31

The splicing factor Prp31 is essential for photoreceptor development in Drosophila

Comprehensive SNP-chip for retinitis pigmentosa-Leber congenital amaurosis diagnosis: new mutations and detection of mutational founder effects

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