Alternatively Spliced Genes

Wu, Jane Y.; Lu, Yuan; Havlioglu, Necat

doi:10.1002/3527600906.mcb.200300189

Cited by 9 publications

(14 citation statements)

References 290 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Defective pre-mRNA splicing has been associated with the pathogenesis of neurodegenerative disorders including amyotrophic lateral sclerosis, spinal muscular atrophy and dementia (Grabowski and Black, 2001;Faustino and Cooper, 2003;Wu et al, 2004). Both cis-acting and trans-acting mutations that cause defective pre-mRNA splicing have been identified in patients with retinal degeneration.…”

Section: Discussionmentioning

confidence: 99%

“…The splicing reaction occurs in spliceosomes, the large RNA-protein complexes that contain pre-mRNA, five small nuclear ribonucleoprotein (snRNP) particles, U1, U2, U4/U6 and U5, as well as a number of non-snRNP protein factors (Burge et. al., 1999;Hastings and Krainer 2001;Zhou et al, 2002;Wu et al, 2004). Following the initial recognition of splice sites by U1snRNP and U2snRNP together with early-step protein factors, the assembly and incorporation of the U4/U6.U5 tri-snRNP is crucial for the formation of the catalytically active center in the spliceosome.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa

Mordes

et al. 2007

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

Several ubiquitously expressed genes encoding pre-mRNA splicing factors have been associated with autosomal dominant retinitis pigmentosa (adRP), including PRPF31, PRPF3 and PRPF8. Molecular mechanisms by which defects in pre-mRNA splicing factors cause photoreceptor degeneration are not clear. To investigate the role of pre-mRNA splicing in photoreceptor gene expression and function, we have begun to search for photoreceptor genes whose pre-mRNA splicing are affected by mutations in PRPF31. Using an immunoprecipitation-coupled-microarray method, we identified a number of transcripts associated with PRPF31-containing complexes, including peripherin/RDS, FSCN2 and other photoreceptor-expressed genes. We constructed minigenes to study the effects of PRPF31 mutations on the pre-mRNA splicing of these photoreceptor specific genes. Our experiments demonstrated that mutant PRPF31 significantly inhibited pre-mRNA splicing of RDS and FSCN2. These observations suggest a functional link between ubiquitously expressed and retina-specifically expressed adRP genes. Our results indicate that PRPF31 mutations lead to defective pre-mRNA splicing of photoreceptor-specific genes and that the ubiquitously expressed adRP gene, PRPF31, is critical for pre-mRNA splicing of a subset of photoreceptor genes. Our results provide an explanation for the photoreceptor-specific phenotype of PRPF31 mutations.Keywords pre-mRNA splicing; autosomal dominant retinitis pigmentosa (adRP); PRPF31; Fascin (FSCN2);

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa

Mordes

et al. 2007

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…The vast majority of mammalian transcription units contain introns that must be accurately excised to form functional mRNA. Pre-mRNA splicing reaction occurs in spliceosomes, the large RNA-protein complexes containing pre-mRNA, five small nuclear ribonucleoprotein (snRNP) particles, U1, U2, U4/U6, and U5, as well as a large number of accessory protein factors (Burge et al, 1999;Hastings and Krainer 2001;Zhou et al, 2002;Wu et al, 2004). Proteins required for the formation of stable U4/U6 snRNPs and for assembly of the U4/U6.U5 tri-snRNP have been identified, including HPRP3, PRPC8, and PRPF31.…”

Section: Introductionmentioning

confidence: 99%

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

Lu¹,

Kawada²,

Havlioglu³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

Mutations in human PRPF31 gene have been identified in patients with autosomal dominant retinitis pigmentosa (adRP). To begin to understand mechanisms by which defects in this general splicing factor cause retinal degeneration, we examined the relationship between PRPF31 and pre-mRNA splicing of photoreceptor-specific genes. We used a specific anti-PRPF31 antibody to immunoprecipitate splicing complexes from retinal cells and identified the transcript of rhodopsin gene (RHO) among RNA species associated with PRPF31-containing complexes. Mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of intron 3 in RHO gene. In primary retinal cell cultures, expression of the mutant PRPF31 proteins reduced rhodopsin expression and caused apoptosis of rhodopsinpositive retinal cells. This primary retinal culture assay provides an in vitro model to study photoreceptor cell death caused by PRPF31 mutations. Our results demonstrate that mutations in PRPF31 gene affect RHO pre-mRNA splicing and reveal a link between PRPF31 and RHO, two major adRP genes.

show abstract

“…Such splicing mutations can cause human diseases by four types of mechanisms: exon skipping, intron retention, cryptic splice site activation, or imbalance of different splicing isoforms (for recent reviews, see Refs. [21][22][23]. The importance of maintaining the delicate balance of different splicing isoforms has only begun to be appreciated.…”

Section: Discussionmentioning

confidence: 99%

“…Many of these trans-acting factors were initially identified using biochemical approaches (reviewed in Refs. [21][22][23]. In this study, we have developed an expression cloning approach using a tau exon 10 splicing green fluorescent protein (GFP) reporter, Tau4R-GFP, in which GFP expression was dependent on the tau exon 10 inclusion.…”

mentioning

confidence: 99%

RBM4 Interacts with an Intronic Element and Stimulates Tau Exon 10 Inclusion

Kar

Havlioglu

Tarn

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Tau protein, which binds to and stabilizes microtubules, is critical for neuronal survival and function. In the human brain, tau pre-mRNA splicing is regulated to maintain a delicate balance of exon 10-containing and exon 10-skipping isoforms. Splicing mutations affecting tau exon 10 alternative splicing lead to tauopathies, a group of neurodegenerative disorders including dementia. Molecular mechanisms regulating tau alternative splicing remain to be elucidated. In this study, we have developed an expression cloning strategy to identify splicing factors that stimulate tau exon 10 inclusion. Using this expression cloning approach, we have identified a previously unknown tau exon 10 splicing regulator, RBM4 (RNA binding motif protein 4). In cells transfected with a tau minigene, RBM4 overexpression leads to an increased inclusion of exon 10, whereas RBM4 down-regulation decreases exon 10 inclusion. The activity of RBM4 in stimulating tau exon 10 inclusion is abolished by mutations in its RNA-binding domain. A putative intronic splicing enhancer located in intron 10 of the tau gene is required for the splicing stimulatory activity of RBM4. Immunohistological analyses reveal that RBM4 is expressed in the human brain regions affected in tauopathy, including the hippocampus and frontal cortex. Our study demonstrates that RBM4 is involved in tau exon 10 alternative splicing. Our work also suggests that down-regulating tau exon 10 splicing activators, such as RBM4, may be of therapeutic potential in tauopathies involving excessive tau exon 10 inclusion.Microtubule-associated protein tau regulates the organization and stability of microtubules (MTs) 2 in the neurons. In humans, the Tau protein is encoded by a single gene on chromosome 17. The tau gene is expressed at a high level in neurons and at lower levels in glia and certain nonneuronal cells. Involved in maintaining cell morphology, axonal extension, and vesicle transport, Tau is critical for the formation and function of neurons (1-3) (for recent reviews, see . The expression of the tau gene is under complex regulation at multiple steps, including both post-transcriptional and post-translational levels. In the human brain, six tau isoforms are expressed as a result of alternative splicing of exons 2, 3, and 10 (10-12). Alternative splicing of exon 10 (Ex10), which encodes for one of the four MT-binding domains, gives rise to tau isoforms containing either four MT-binding repeats (Tau4R, Ex10+) or three * This work was supported by National Institutes of Health Grants AG17518, EY014576, and GM070967 (to J. Y. W.), the Society for Progressive Supranuclear Palsy, Muscular Dystrophy Association (to J. Y. W.), and by a scholar award from the Leukemia Society of America (to J. Y. W.).1To whom correspondence should be addressed: Northwestern University Feinberg School of Medicine, Center for Genetic Medicine, 303 E. Superior St., Chicago,; E-mail: jane-wu@northwestern.edu. 2 The abbreviations used are: MT, microtubule; Ex10, exon 10; FTDP-17, frontotemporal dem...

show abstract

Alternatively Spliced Genes

Cited by 9 publications

References 290 publications

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa

Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa

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

RBM4 Interacts with an Intronic Element and Stimulates Tau Exon 10 Inclusion

Contact Info

Product

Resources

About