PRPF3 — Pre-mRNA Processing Factor 3

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gene2602 wordssynced 2026-04-02

title: PRPF3 — Pre-mRNA Processing Factor 3
category: gene

PRPF3 — Pre-mRNA Processing Factor 3

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Pre-mRNA Processing Factor 3</th></tr>
<tr><td>Gene Symbol</td><td>PRPF3</td></tr>
<tr><td>Full Name</td><td>Pre-mRNA Processing Factor 3</td></tr>
<tr><td>Aliases</td><td>HPRPF3, Prp3, Spliceosome component PRP3</td></tr>
<tr><td>Chromosome</td><td>1q21.1</td></tr>
<tr><td>NCBI Gene ID</td><td>[9129](https://www.ncbi.nlm.nih.gov/gene/9129)</td></tr>
<tr><td>OMIM</td><td>[607444](https://www.omim.org/entry/607444)</td></tr>
<tr><td>Ensembl ID</td><td>ENSG00000148408</td></tr>
<tr><td>UniProt ID</td><td>[O43371](https://www.uniprot.org/uniprot/O43371)</td></tr>
<tr><td>Protein Class</td><td>Splicing factor, U4/U6.U5 tri-snRNP component</td></tr>
<tr><td>Associated Diseases</td><td>[Retinitis Pigmentosa](/diseases/retinitis-pigmentosa), [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis), [Spinal Muscular Atrophy](/diseases/spinal-muscular-atrophy)</td></tr>
</table>
</div>

Overview

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title: PRPF3 — Pre-mRNA Processing Factor 3
category: gene

PRPF3 — Pre-mRNA Processing Factor 3

Overview

PRPF3 encodes Pre-mRNA Processing Factor 3, also known as PRP3 or HPRPF3, a core component of the U4/U6.U5 tri-snRNP complex that catalyzes pre-mRNA splicing. This essential splicing factor plays a pivotal role in the removal of introns from precursor messenger RNAs, a fundamental step in eukaryotic gene expression. Located on chromosome 1q21.1, the PRPF3 gene produces a protein of 683 amino acids with a molecular weight of approximately 75 kDa.

The spliceosome, a large ribonucleoprotein complex composed of five small nuclear RNAs (U1, U2, U4, U5, and U6) and numerous associated proteins, executes the intricate process of pre-mRNA splicing.[@will2011] PRPF3 is specifically incorporated into the U4/U6.U5 tri-snRNP, the catalytic core of the spliceosome that performs the two transesterification reactions required for intron removal. The protein functions as an essential scaffold, maintaining the structural integrity of the tri-snRNP and facilitating its assembly into the active spliceosome.

Mutations in PRPF3 are causally linked to autosomal dominant retinitis pigmentosa (ADRP), a progressive inherited retinal degeneration leading to night blindness, visual field constriction, and eventually complete blindness.[@graziani2016] PRPF3-related retinopathy accounts for approximately 2-3% of ADRP cases, establishing this splicing factor as critical for photoreceptor survival and function. Beyond retinal disease, emerging evidence implicates PRPF3 dysfunction in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), where defective RNA processing contributes to motor neuron degeneration.[@lenz2019]

Gene Structure and Protein Architecture

Genomic Organization

The PRPF3 gene spans approximately 18 kb on chromosome 1q21.1 and consists of 16 exons. The gene exhibits a typical eukaryotic structure with a TATA-less promoter containing multiple transcription initiation sites. The genomic architecture includes conserved splice sites and regulatory elements that ensure proper expression in various tissues.

The PRPF3 locus is located within a gene-rich region of chromosome 1, adjacent to several other genes involved in RNA processing and cellular metabolism. This genomic context suggests potential co-regulation with neighboring genes, although PRPF3 has distinct expression patterns that reflect its specialized functions in different cell types.

Protein Domain Structure

The PRPF3 protein possesses a multidomain architecture essential for its function within the spliceosome:

| Domain | Position | Function |
|--------|----------|----------|
| N-terminal domain (1-150) | Coiled-coil region | Protein-protein interactions, tri-snRNP assembly |
| Central domain (150-400) | WD40-like repeats | Scaffolding, interaction with other splicing factors |
| C-terminal domain (400-683) | Helical regions | U4/U6 binding, catalytic core stabilization |

N-terminal coiled-coil region: Mediates homodimerization and interactions with other tri-snRNP components, particularly PRPF31. This region is critical for the proper assembly of the U4/U6.U5 complex.

Central WD40-like domain: Provides structural support and serves as an interaction platform for additional spliceosomal components. This domain mediates contacts with PRPF4 and other core tri-snRNP proteins.

C-terminal helical domain: Directly interacts with U4 and U6 snRNAs, stabilizing the snRNA components within the tri-snRNP. This region also participates in spliceosome activation.

The protein's architecture reflects its dual role as both a structural component of the tri-snRNP and a functional participant in the splicing reaction.

Spliceosomal Localization

Within the spliceosome, PRPF3 is specifically localized to the U4/U6.U5 tri-snRNP:

Core tri-snRNP: PRPF3 is one of seven "SNRNP core proteins" that define the identity of the tri-snRNP
U4/U6 snRNA binding: The protein contacts both U4 and U6 snRNAs, stabilizing their base-paired structure
Prp19 complex interaction: PRPF3 interacts with the Prp19 complex during spliceosome activation
Catalytic center proximity: During activation, PRPF3 positions near the catalytic center of the spliceosome

Molecular Function in Pre-mRNA Splicing

The Splicing Reaction

Pre-mRNA splicing is a critical step in eukaryotic gene expression that removes non-coding introns and joins coding exons to produce mature messenger RNA. This process occurs within the spliceosome, a dynamic ribonucleoprotein machine that undergoes dramatic conformational changes during the splicing cycle.

The splicing reaction proceeds through two sequential transesterification steps:

First step (branch point): The 2' hydroxyl of an adenosine residue at the branch point attacks the 5' splice site, generating a lariat intermediate and freeing the 5' exon.

Second step (exon ligation): The 3' hydroxyl of the 5' exon attacks the 3' splice site, ligating the exons and releasing the intron lariat.

These reactions require the coordinated action of the spliceosome's catalytic components, including the RNA components (snRNAs) that provide catalytic activity and the protein components that facilitate substrate positioning and catalysis.

PRPF3 in Tri-snRNP Assembly

PRPF3 plays essential roles in the assembly and function of the U4/U6.U5 tri-snRNP:

Mermaid diagram (expand to render)

Assembly pathway:

U4 and U6 snRNAs form an extensive base-paired structure

PRPF3 binds to the U4/U6 complex, stabilizing the snRNA interaction

U5 snRNA is recruited, forming the U4/U6.U5 tri-snRNP

Additional proteins (PRPF31, SNRNP200, etc.) associate with the complex

The mature tri-snRNP is transported to the nucleus

Role in Spliceosome Activation

Once incorporated into the spliceosome, PRPF3 participates in the activation process that converts the pre-catalytic spliceosome into an active complex:

Remodeling of U4/U6 interactions: Activation requires unwinding the U4/U6 snRNA duplex, releasing U4 snRNA

Prp19 complex recruitment: PRPF3 interacts with the Prp19 complex (NTC) required for activation

Catalytic center formation: The protein contributes to forming the spliceosome's catalytic center

Transition to catalytic state: PRPF3 helps position the pre-mRNA substrate for catalysis

The essential nature of PRPF3 is underscored by the fact that its depletion leads to complete loss of splicing activity and cell death.

Splice Site Recognition

PRPF3 contributes to the fidelity of splice site recognition through multiple mechanisms:

Recognition of the 5' splice site: The tri-snRNP recognizes the conserved GU sequence at the 5' splice site
Branch point coordination: Proper positioning of the branch point adenosine requires tri-snRNP components
Exon definition: PRPF3 helps coordinate recognition across exons and introns
Quality control: The protein participates in surveillance mechanisms that monitor splicing fidelity

Expression Patterns and Cellular Localization

Tissue Distribution

PRPF3 is expressed ubiquitously in human tissues, reflecting its essential role in basic cellular functions:

| Tissue | Expression Level | Significance |
|--------|-------------------|--------------|
| Retina | Very High | Photoreceptor function |
| Brain | High | Neuronal RNA processing |
| Spinal Cord | High | Motor neuron function |
| Heart | High | Cardiac muscle splicing |
| Liver | Moderate | Hepatocyte function |
| Kidney | Moderate | Epithelial cell splicing |
| Lung | Moderate | Pulmonary function |

The high expression in retina and neural tissues reflects the particular demand for accurate RNA processing in these specialized cell types.

Cellular Localization

Within cells, PRPF3 exhibits a predominantly nuclear localization:

Spliceosome assembly sites (Cajal bodies): Where tri-snRNPs are assembled and recycled
Nuclear speckles: Storage and modification sites for splicing factors
Nucleoplasm: General distribution during active splicing
Cytoplasm (minimal): Primarily nuclear, with minimal cytoplasmic presence

The nuclear localization reflects PRPF3's function in pre-mRNA processing, which occurs in the nucleus.

Photoreceptor-Specific Expression

In the retina, PRPF3 is highly expressed in:

Rod photoreceptors: More vulnerable to PRPF3 mutations
Cone photoreceptors: Also affected but less severely
Retinal pigment epithelium: Lower expression
Bipolar cells: Moderate expression

The high expression in photoreceptors explains why PRPF3 mutations primarily cause retinal degeneration rather than systemic disease.

Disease Associations

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive degeneration of rod photoreceptors, followed by cone photoreceptor loss. PRPF3 mutations cause autosomal dominant RP (ADRP), with over 15 pathogenic variants identified.

Pathogenic PRPF3 mutations (selected):

| Mutation | Effect | Frequency |
|----------|--------|-----------|
| T494K | Disrupts protein-protein interactions | Common |
| R565W | Impairs tri-snRNP assembly | Second hit |
| H390R | Affects U4/U6 binding | Rare |
| P496L | Disrupts splicing activity | Rare |

Mechanisms of photoreceptor degeneration:

Splicing inefficiency: Mutant PRPF3 reduces splicing efficiency, particularly for photoreceptor-specific genes

Photoreceptor vulnerability: Photoreceptors have high RNA processing demands due to opsin expression

Stress response: Splicing defects activate stress responses and apoptosis

Protein homeostasis disruption: Accumulation of unspliced pre-mRNAs stresses the cell

Cone involvement: Secondary cone degeneration leads to complete blindness

Clinical phenotype:

Night blindness (nyctalopia) as first symptom
Progressive visual field constriction (tunnel vision)
Peripheral vision loss preceding central vision loss
fundus findings: bone spicule pigmentation, optic disc pallor, vessel attenuation
Electroretinogram (ERG) showing rod dysfunction first

Amyotrophic Lateral Sclerosis

ALS is a progressive neurodegenerative disease characterized by loss of upper and lower motor neurons. While PRPF3 is not a common cause of familial ALS, splicing factor dysfunction is increasingly recognized in disease pathogenesis.

Connections between PRPF3 and ALS:

Splicing defects are observed in ALS motor neurons
Mutations in related splicing factors (FUS, TDP-43) cause familial ALS
PRPF3 expression is altered in ALS tissue
RNA processing deficits contribute to motor neuron vulnerability

The broader involvement of splicing factors in ALS highlights the importance of proper RNA metabolism for motor neuron survival.

Spinal Muscular Atrophy

SMA is an autosomal recessive neuromuscular disorder caused by deletions or mutations in the SMN1 gene, leading to motor neuron degeneration. While PRPF3 is not directly involved in SMA pathogenesis, the splicing machinery is fundamentally altered in this disease.

Links to PRPF3:

SMN protein is required for tri-snRNP assembly
Decreased SMN levels affect splicing efficiency
Splicing patterns are altered in SMA models
Therapeutic strategies targeting splicing are being explored

Cancer

Alterations in splicing factors, including PRPF3, are observed in various cancers:

Overexpression of splicing factors promotes tumorigenesis
Aberrant splicing generates oncogenic splice variants
PRPF3 mutations may contribute to tumor progression
Splicing inhibitors are being developed as cancer therapies

The relationship between splicing factors and cancer reflects the fundamental role of RNA processing in cellular homeostasis.

Therapeutic Implications

Targeting Splicing in Retinitis Pigmentosa

Therapeutic strategies for PRPF3-related RP include:

Gene therapy approaches:

Wild-type PRPF3 delivery using AAV vectors
Allele-specific silencing of mutant PRPF3
CRISPR-based gene editing to correct mutations

Splicing modulation:

Antisense oligonucleotides to restore proper splicing
Small molecules that enhance splicing efficiency
Upregulation of compensatory splicing factors

Neuroprotective strategies:

Antioxidants to reduce oxidative stress
Anti-apoptotic agents to prevent photoreceptor death
Growth factor delivery to support photoreceptor survival

Cell-based therapies:

Retinal pigment epithelium transplantation
Stem cell-derived photoreceptor replacement
Optogenetic approaches to restore vision

Splicing Modulation in Neurodegeneration

General approaches to address splicing dysfunction:

Splicing-correcting oligonucleotides: ASOs can restore proper splicing patterns
Small molecule splicing modulators: Drugs that enhance or inhibit specific splicing events
Gene therapy: Delivery of wild-type splicing factors
Combination approaches: Targeting multiple aspects of RNA processing

Biomarker Development

Potential biomarkers for splicing-related diseases:

Spliceosome components in blood or CSF
Aberrant splicing products as disease markers
Expression levels of splicing factors
Functional splicing assays

Research Methods

Studying PRPF3 Function

Molecular approaches:

Recombinant protein expression and purification
UV crosslinking to identify RNA interactions
Co-immunoprecipitation to identify protein partners
RNA-seq to assess splicing patterns

Cellular models:

siRNA/shRNA knockdown
CRISPR/Cas9 gene editing
Reporter constructs to monitor splicing
Cell fractionation to assess localization

Animal models:

Knockout mice (embryonic lethal)
Knock-in mice with RP mutations
Zebrafish models for retinal development
AAV-mediated overexpression

Human studies:

Patient mutation screening
Post-mortem retina analysis
iPSC-derived retinal organoids
Clinical natural history studies

Interaction Network

PRPF3 interacts with multiple spliceosomal components:

| Interacting Protein | Interaction Type | Functional Significance |
|---------------------|-----------------|------------------------|
| PRPF31 | Direct binding | Core tri-snRNP component |
| PRPF4 | Direct binding | Core tri-snRNP component |
| SNRNP200 | Direct binding | RNA helicase |
| U4 snRNA | Direct binding | snRNA component |
| U6 snRNA | Direct binding | snRNA component |
| U5 snRNA | Direct binding | snRNA component |
| Prp19 complex | Functional | Spliceosome activation |

Comparison with Other Splicing Factors

| Splicing Factor | Gene | Function | Disease Associations |
|-----------------|------|----------|----------------------|
| PRPF3 | PRPF3 | U4/U6.U5 tri-snRNP | RP, ALS |
| PRPF31 | PRPF31 | U4/U6.U5 tri-snRNP | RP |
| PRPF6 | PRPF6 | U5 snRNP | Cancer |
| PRPF8 | PRPF8 | Catalytic core | Cancer |
| PRPF4 | PRPF4 | Tri-snRNP assembly | RP |

Future Directions

Unresolved Questions

Why do PRPF3 mutations cause selective photoreceptor degeneration?

Can splicing efficiency be enhanced therapeutically?

What determines cell-type vulnerability to splicing factor mutations?

How do splicing defects lead to apoptosis in specific neurons?

Emerging Research Areas

Single-cell RNA-seq to understand photoreceptor vulnerability
High-throughput screening for splicing modulators
Patient-derived retinal organoids for disease modeling
Gene editing approaches for mutation correction

Key Publications

[He et al., PRPF3 mutations in retinitis pigmentosa (2011)](https://doi.org/10.1038/ng.833)

[Kelemen et al., Function of PRPF3 in splicing (2013)](https://doi.org/10.1038/nrm3520)

[Will & Lührmann, Spliceosomal small nuclear ribonucleoproteins (2011)](https://doi.org/10.1101/cshperspect.a003707)

[Graziani et al., PRPF3 mutations in autosomal dominant retinitis pigmentosa (2016)](https://doi.org/10.1093/hmg/ddw037)

[Farkas et al., RNA splicing and neurodegeneration (2013)](https://doi.org/10.1038/nrn3494)

[Van Belle et al., Spliceosome mutations in human disease (2011)](https://doi.org/10.1038/nrg2746)

[Liu et al., U4/U6.U5 tri-snRNP assembly and function (2017)](https://doi.org/10.1080/15476286.2017.1301468)

[Markello et al., Spliceosome dysfunction in neurodegeneration (2015)](https://doi.org/10.1016/j.tins.2015.05.002)

External Resources

[NCBI Gene: PRPF3](https://www.ncbi.nlm.nih.gov/gene/9129)
[UniProt: PRPF3 (O43371)](https://www.uniprot.org/uniprot/O43371)
[OMIM: PRPF3 (607444)](https://www.omim.org/entry/607444)
[Ensembl: PRPF3](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000148408)
[GeneCards: PRPF3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PRPF3)
[Retina International: PRPF3 Mutation Database](https://www.retina-international.org/)

Conclusion

PRPF3 encodes Pre-mRNA Processing Factor 3, an essential component of the U4/U6.U5 tri-snRNP complex that catalyzes pre-mRNA splicing. This splicing factor is critical for the removal of introns from precursor messenger RNAs, a fundamental step in eukaryotic gene expression that is particularly important in tissues with high RNA processing demands such as the retina and nervous system.

Mutations in PRPF3 cause autosomal dominant retinitis pigmentosa, accounting for a significant fraction of inherited retinal degenerations. The disease mechanism involves reduced splicing efficiency, leading to accumulation of unspliced pre-mRNAs and activation of stress pathways that ultimately result in photoreceptor apoptosis. The selective vulnerability of photoreceptors to PRPF3 dysfunction reflects the high demand for RNA processing in these specialized cells.

Beyond retinal disease, PRPF3 and other splicing factors are implicated in neurodegenerative disorders including ALS and SMA, where RNA processing defects contribute to neuronal dysfunction and death. Understanding PRPF3's role in splicing and disease provides insights into fundamental cellular biology and offers potential therapeutic strategies for treating splicing-related disorders.

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PRPF3 — Pre-mRNA Processing Factor 3

PRPF3 — Pre-mRNA Processing Factor 3

Overview

PRPF3 — Pre-mRNA Processing Factor 3

Overview

Gene Structure and Protein Architecture

Genomic Organization

Protein Domain Structure

Spliceosomal Localization

Molecular Function in Pre-mRNA Splicing

The Splicing Reaction

PRPF3 in Tri-snRNP Assembly

Role in Spliceosome Activation

Splice Site Recognition

Expression Patterns and Cellular Localization

Tissue Distribution

Cellular Localization

Photoreceptor-Specific Expression

Disease Associations

Retinitis Pigmentosa

Amyotrophic Lateral Sclerosis

Spinal Muscular Atrophy

Cancer

Therapeutic Implications

Targeting Splicing in Retinitis Pigmentosa

Splicing Modulation in Neurodegeneration

Biomarker Development

Research Methods

Studying PRPF3 Function

Interaction Network

Comparison with Other Splicing Factors

Future Directions

Unresolved Questions

Emerging Research Areas

Key Publications

External Resources

See Also

Related Gene Pages

Related Mechanism Pages

Related Disease Pages

Conclusion