🔗

Mappings

MONDO

MONDO:0010828 retinitis pigmentosa 11 Not Yet Curated

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

PRPF31-RP shows frequent, well-documented incomplete penetrance: some heterozygous mutation carriers remain entirely asymptomatic (complete non-penetrance), while others show highly variable severity within the same family carrying the identical variant. This is a rare true non-penetrance phenomenon in Mendelian disease, distinct from variable expressivity, and complicates both genetic diagnosis and prevalence estimation.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:26853529 SUPPORT Human Clinical

"An intriguing feature of RP11 is the presence of non-penetrance, which has been observed in the majority of PRPF31 mutation-carrying families. In contrast to variable expressivity, which is highly pervasive, true non-penetrance is a very rare phenomenon in Mendelian disorders."

Establishes non-penetrance (distinct from variable expressivity) as a defining and unusually common feature of PRPF31-RP among Mendelian disorders.

PMID:32014492 SUPPORT Human Clinical

"obligate carriers may be totally asymptomatic, showing complete non-penetrance"

Confirms that some obligate PRPF31 mutation carriers show complete non-penetrance, contributing to underestimation of disease prevalence.

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Discussions and Knowledge Gaps

1

Are photoreceptors or the retinal pigment epithelium the primary cell type affected by PRPF31 haploinsufficiency?

KNOWLEDGE GAP OPEN gap_prpf31_photoreceptor_vs_rpe_primary_site

Attached to

pathophysiology#Impaired Pre-mRNA Splicing of Photoreceptor Genes

PRPF31 is ubiquitously expressed and its core splicing function is not retina-specific, yet disease is confined to the retina. Some studies report retina-enriched PRPF31 expression while others find no tissue enrichment, and separate lines of evidence implicate the retinal pigment epithelium rather than photoreceptors as the primary affected tissue. Resolving this is important for interpreting model systems and designing cell-type-appropriate gene therapy delivery.

Show evidence (1 reference)

PMID:32014492 SUPPORT Human Clinical

"It remains unclear whether the photoreceptor cells are the primary affected cells in RP associated with PRPF31, with a number of studies suggesting that the RPE is the primary affected tissue"

States the open question directly: whether photoreceptors or RPE are the primary PRPF31-RP-affected cell type remains unresolved.

⚙

Pathophysiology

4

PRPF31 Haploinsufficiency and Tri-snRNP Assembly Defect

PRPF31 encodes a component of the U4/U6.U5 tri-snRNP spliceosomal particle, bridging the U4/U6 di-snRNP to U5 during spliceosome assembly. Heterozygous pathogenic variants -- nonsense, frameshift, splice-site, and missense substitutions that reduce protein solubility -- lower functional PRPF31 protein levels. Missense variants act primarily through reduced protein solubility causing insufficiency of functional protein, with a minor direct negative effect on splicing function, rather than a purely dominant-negative mechanism.

spliceosomal tri-snRNP complex assembly GO:0000244 ↓ DECREASED

Downstream

Impaired Pre-mRNA Splicing of Photoreceptor Genes Reduced functional PRPF31 and consequent tri-snRNP assembly deficits preferentially compromise splicing capacity for the high-volume, alternatively-spliced pre-mRNA burden characteristic of photoreceptors.

Show evidence (2 references)

PMID:11545739 SUPPORT Human Clinical

"The level of sequence identity to the yeast PRP31 gene indicates that PRPF31 is also likely to be involved in pre-mRNA splicing."

Original gene-identification study establishing PRPF31 as a pre-mRNA splicing factor homologous to yeast PRP31.

PMID:18431455 SUPPORT In Vitro

"The RP11 missense mutations exert their pathology mainly via a mechanism based on protein insufficiency due to protein insolubility, but there is also a minor direct negative effect on function."

Establishes protein insufficiency from reduced solubility, not a purely dominant-negative mechanism, as the predominant pathogenic route for RP11 missense variants.

CNOT3-Mediated Modulation of Wild-Type PRPF31 Expression

Penetrance of PRPF31 mutations is determined by a trans-acting genetic modifier: CNOT3, a subunit of the CCR4-NOT transcription complex, binds the PRPF31 promoter and transcriptionally represses it. CNOT3 expression is inversely correlated with PRPF31 expression across family members. In asymptomatic mutation carriers, low CNOT3 expression permits higher transcription from the wild-type PRPF31 allele, raising total functional PRPF31 above the pathogenic threshold and preventing retinal degeneration despite carrying the same causative variant as affected relatives.

spliceosomal tri-snRNP complex assembly GO:0000244 ↑ INCREASED

Downstream

Impaired Pre-mRNA Splicing of Photoreceptor Genes Low CNOT3 expression raises wild-type PRPF31 output above the pathogenic haploinsufficiency threshold, mitigating (rather than driving) the downstream splicing defect -- the mechanistic basis of non-penetrance in asymptomatic carriers.

Show evidence (2 references)

PMID:23144630 SUPPORT Human Clinical

"CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31..."

Establishes CNOT3 as the main penetrance modifier gene for PRPF31 mutations, acting via direct promoter binding and transcriptional repression.

PMID:23144630 SUPPORT In Vitro

"In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31"

Demonstrates the mechanistic basis of non-penetrance: low CNOT3 expression in asymptomatic carriers permits higher wild-type PRPF31 output that compensates for the mutant allele.

Impaired Pre-mRNA Splicing of Photoreceptor Genes

Photoreceptors are among the most transcriptionally and metabolically active cells in the body, with an unusually high burden of pre-mRNA splicing to sustain phototransduction-gene expression. Reduced PRPF31 availability significantly inhibits splicing of intron 3 in the rhodopsin (RHO) gene, linking PRPF31 dysfunction mechanistically to RHO, another major adRP gene. Whether photoreceptors themselves or the retinal pigment epithelium are the primary affected cell type remains an open question in the field.

Retinal rod cell CL:0000604

mRNA splicing, via spliceosome GO:0000398 ↓ DECREASED

Downstream

Rod Photoreceptor Apoptosis Impaired splicing of photoreceptor-specific transcripts, particularly rhodopsin, reduces expression of essential phototransduction proteins and triggers photoreceptor cell death.

Show evidence (1 reference)

PMID:15659613 SUPPORT In Vitro

"Mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of intron 3 in RHO gene."

Directly demonstrates that mutant PRPF31 impairs splicing of the RHO transcript, mechanistically linking the two major adRP genes.

Rod Photoreceptor Apoptosis

Reduced rhodopsin expression secondary to defective PRPF31-dependent splicing causes apoptosis of rhodopsin-positive retinal cells, producing progressive rod photoreceptor loss with secondary cone involvement and the classic retinitis pigmentosa clinical phenotype.

Retinal rod cell CL:0000604 Retinal cone cell CL:0000573

apoptotic process GO:0006915 ↑ INCREASED

Show evidence (1 reference)

PMID:15659613 SUPPORT In Vitro

"In primary retinal cell cultures, expression of the mutant PRPF31 proteins reduced rhodopsin expression and caused apoptosis of rhodopsin-positive retinal cells."

Direct experimental demonstration that mutant PRPF31 expression reduces rhodopsin and causes apoptosis of rhodopsin-expressing retinal cells.

⬡

Pathograph

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Phenotypes

5

Eye 4

Night blindness VERY_FREQUENT Nyctalopia HP:0000662

Show evidence (1 reference)

PMID:32014492 SUPPORT Human Clinical

"Age of onset of first symptoms (usually night-blindness) is lowest in patients with nonsense, frameshift or indel variants, with median age of onset between 8 and 12 years of age."

Establishes night blindness as the usual first symptom, with age of onset varying significantly by variant class.

Progressive peripheral visual field loss VERY_FREQUENT Constriction of peripheral visual field HP:0001133

Show evidence (1 reference)

PMID:32014492 SUPPORT Human Clinical

"patients with nonsense, frameshift or splice variants were diagnosed at a median age of 20–30 years (usually because of loss of peripheral vision alongside night blindness)"

Confirms peripheral visual field loss, alongside night blindness, as a principal driver of clinical diagnosis in PRPF31-RP.

Rod-cone dystrophy VERY_FREQUENT HP:0000510

Show evidence (1 reference)

PMID:30582903 SUPPORT Human Clinical

"Only 6 patients had a non-recordable cone response on their initial visit, suggesting that rod function deteriorates before cone function."

Natural-history cohort study directly demonstrates the rod-predominant dystrophy pattern: cone responses remained recordable in most patients while rod function deteriorated first.

Abnormal electroretinogram VERY_FREQUENT HP:0000512

Show evidence (1 reference)

PMID:30582903 SUPPORT Human Clinical

"Regarding the rod and cone ERG waveforms, 21 patients had no detectable rod b-wave at their initial visit, while 5 patients had rod b-wave amplitude severely reduced in amplitude."

Clinical cohort study directly documents rod-predominant ERG abnormality (non-detectable or severely reduced rod b-wave) in affected PRPF31 mutation carriers.

Other 1

Spicular retinal pigmentation FREQUENT Spicular pigmentation of the retina HP:0007737

Show evidence (1 reference)

PMID:30582903 SUPPORT Human Clinical

"Fundus appearance of all affected individuals was consistent with retinitis pigmentosa, with waxy pallor of the optic nerve, retinal vessel attenuation, and bone spicule pigment"

Natural-history cohort study directly documents bone-spicule pigment on fundus exam in all affected PRPF31 mutation carriers.

🧬

Genetic Associations

2

PRPF31

Gene: PRPF31 hgnc:15446 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:11545739 SUPPORT Human Clinical

"We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138)."

Original identification of PRPF31 as the RP11 disease gene.

CNOT3

Gene: CNOT3 hgnc:7879 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:23144630 SUPPORT Human Clinical

"we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression"

Identifies CNOT3 as the primary trans-acting modifier of PRPF31-RP penetrance.

💊

Medical Actions

3

PRPF31 Gene Augmentation Therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Investigational AAV-mediated gene augmentation, delivering a wild-type copy of PRPF31, is under active preclinical investigation as a mutation-independent approach exploiting the haploinsufficiency mechanism of disease.

Show evidence (1 reference)

PMID:35974011 SUPPORT In Vitro

"The rescue of RPE and photoreceptor defective phenotypes by PRPF31 gene augmentation provide the proof of concept"

Demonstrates proof-of-concept rescue of both RPE and photoreceptor defective phenotypes by AAV-mediated PRPF31 gene augmentation in patient-derived organoid models.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling is particularly important in PRPF31-RP given its incomplete penetrance -- asymptomatic obligate carriers can still transmit disease to offspring, complicating risk assessment and segregation analysis.

Low Vision Rehabilitation

Action: low vision rehabilitation Ontology label: Supportive Care NCIT:C15747

Supportive low-vision aids and rehabilitation; no approved disease-modifying therapy is currently available for PRPF31-related retinopathy.

{ }

Source YAML

click to show

name: PRPF31-Related Retinopathy
creation_date: "2026-07-09T00:00:00Z"
category: Mendelian
description: >
  PRPF31-related retinopathy (retinitis pigmentosa 11, RP11) is an autosomal
  dominant inherited retinal dystrophy caused by heterozygous variants in
  PRPF31, which encodes a component of the U4/U6.U5 tri-snRNP spliceosomal
  complex required for pre-mRNA splicing. PRPF31 is the second most common
  genetic cause of autosomal dominant retinitis pigmentosa in most populations.
  Pathogenic variants act through haploinsufficiency: they reduce functional
  PRPF31 protein below the threshold required for efficient spliceosome
  assembly, preferentially disrupting splicing of highly-expressed
  photoreceptor transcripts such as rhodopsin and driving rod photoreceptor
  degeneration. RP11 is distinguished among Mendelian disorders by frequent,
  well-characterized incomplete penetrance: some heterozygous mutation
  carriers remain entirely asymptomatic, an outcome modulated by trans-acting
  expression of the wild-type PRPF31 allele.
disease_term:
  preferred_term: PRPF31-related retinopathy
  term:
    id: MONDO:0800395
    label: PRPF31-related retinopathy
synonyms:
- Retinitis Pigmentosa 11
- RP11
- PRPF31 retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010828
      label: retinitis pigmentosa 11
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    notes: >-
      MONDO:0010828 (RP11, OMIM:600138) is the classically-named clinical
      entity and is a child term (is_a) of MONDO:0800395, the broader PRPF31
      gene-series grouping term used as this entry's primary disease_term.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    PRPF31-RP shows frequent, well-documented incomplete penetrance: some
    heterozygous mutation carriers remain entirely asymptomatic (complete
    non-penetrance), while others show highly variable severity within the
    same family carrying the identical variant. This is a rare true
    non-penetrance phenomenon in Mendelian disease, distinct from variable
    expressivity, and complicates both genetic diagnosis and prevalence
    estimation.
  evidence:
  - reference: PMID:26853529
    reference_title: "Variant haploinsufficiency and phenotypic non-penetrance in PRPF31-associated retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An intriguing feature of RP11 is the presence of non-penetrance, which has been observed in the majority of PRPF31 mutation-carrying families. In contrast to variable expressivity, which is highly pervasive, true non-penetrance is a very rare phenomenon in Mendelian disorders."
    explanation: >
      Establishes non-penetrance (distinct from variable expressivity) as a
      defining and unusually common feature of PRPF31-RP among Mendelian
      disorders.
  - reference: PMID:32014492
    reference_title: "Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "obligate carriers may be totally asymptomatic, showing complete non-penetrance"
    explanation: >
      Confirms that some obligate PRPF31 mutation carriers show complete
      non-penetrance, contributing to underestimation of disease prevalence.
pathophysiology:
- name: PRPF31 Haploinsufficiency and Tri-snRNP Assembly Defect
  description: >
    PRPF31 encodes a component of the U4/U6.U5 tri-snRNP spliceosomal
    particle, bridging the U4/U6 di-snRNP to U5 during spliceosome assembly.
    Heterozygous pathogenic variants -- nonsense, frameshift, splice-site, and
    missense substitutions that reduce protein solubility -- lower functional
    PRPF31 protein levels. Missense variants act primarily through reduced
    protein solubility causing insufficiency of functional protein, with a
    minor direct negative effect on splicing function, rather than a purely
    dominant-negative mechanism.
  biological_processes:
  - preferred_term: spliceosomal tri-snRNP complex assembly
    term:
      id: GO:0000244
      label: spliceosomal tri-snRNP complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:11545739
    reference_title: "A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The level of sequence identity to the yeast PRP31 gene indicates that PRPF31 is also likely to be involved in pre-mRNA splicing."
    explanation: >
      Original gene-identification study establishing PRPF31 as a pre-mRNA
      splicing factor homologous to yeast PRP31.
  - reference: PMID:18431455
    reference_title: "Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The RP11 missense mutations exert their pathology mainly via a mechanism based on protein insufficiency due to protein insolubility, but there is also a minor direct negative effect on function."
    explanation: >
      Establishes protein insufficiency from reduced solubility, not a purely
      dominant-negative mechanism, as the predominant pathogenic route for
      RP11 missense variants.
  downstream:
  - target: Impaired Pre-mRNA Splicing of Photoreceptor Genes
    description: >-
      Reduced functional PRPF31 and consequent tri-snRNP assembly deficits
      preferentially compromise splicing capacity for the high-volume,
      alternatively-spliced pre-mRNA burden characteristic of photoreceptors.
- name: CNOT3-Mediated Modulation of Wild-Type PRPF31 Expression
  description: >
    Penetrance of PRPF31 mutations is determined by a trans-acting genetic
    modifier: CNOT3, a subunit of the CCR4-NOT transcription complex, binds
    the PRPF31 promoter and transcriptionally represses it. CNOT3 expression
    is inversely correlated with PRPF31 expression across family members. In
    asymptomatic mutation carriers, low CNOT3 expression permits higher
    transcription from the wild-type PRPF31 allele, raising total functional
    PRPF31 above the pathogenic threshold and preventing retinal degeneration
    despite carrying the same causative variant as affected relatives.
  biological_processes:
  - preferred_term: spliceosomal tri-snRNP complex assembly
    term:
      id: GO:0000244
      label: spliceosomal tri-snRNP complex assembly
    modifier: INCREASED
  evidence:
  - reference: PMID:23144630
    reference_title: "CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression."
    explanation: >
      Establishes CNOT3 as the main penetrance modifier gene for PRPF31
      mutations, acting via direct promoter binding and transcriptional
      repression.
  - reference: PMID:23144630
    reference_title: "CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31"
    explanation: >
      Demonstrates the mechanistic basis of non-penetrance: low CNOT3
      expression in asymptomatic carriers permits higher wild-type PRPF31
      output that compensates for the mutant allele.
  downstream:
  - target: Impaired Pre-mRNA Splicing of Photoreceptor Genes
    description: >-
      Low CNOT3 expression raises wild-type PRPF31 output above the
      pathogenic haploinsufficiency threshold, mitigating (rather than
      driving) the downstream splicing defect -- the mechanistic basis of
      non-penetrance in asymptomatic carriers.
- name: Impaired Pre-mRNA Splicing of Photoreceptor Genes
  description: >
    Photoreceptors are among the most transcriptionally and metabolically
    active cells in the body, with an unusually high burden of pre-mRNA
    splicing to sustain phototransduction-gene expression. Reduced PRPF31
    availability significantly inhibits splicing of intron 3 in the rhodopsin
    (RHO) gene, linking PRPF31 dysfunction mechanistically to RHO, another
    major adRP gene. Whether photoreceptors themselves or the retinal pigment
    epithelium are the primary affected cell type remains an open question in
    the field.
  cell_types:
  - preferred_term: Retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: DECREASED
  evidence:
  - reference: PMID:15659613
    reference_title: "Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutant PRPF31 proteins significantly inhibited pre-mRNA splicing of intron 3 in RHO gene."
    explanation: >
      Directly demonstrates that mutant PRPF31 impairs splicing of the RHO
      transcript, mechanistically linking the two major adRP genes.
  downstream:
  - target: Rod Photoreceptor Apoptosis
    description: >-
      Impaired splicing of photoreceptor-specific transcripts, particularly
      rhodopsin, reduces expression of essential phototransduction proteins
      and triggers photoreceptor cell death.
- name: Rod Photoreceptor Apoptosis
  conforms_to: "photoreceptor_degeneration#Rod Photoreceptor Apoptosis"
  description: >
    Reduced rhodopsin expression secondary to defective PRPF31-dependent
    splicing causes apoptosis of rhodopsin-positive retinal cells, producing
    progressive rod photoreceptor loss with secondary cone involvement and
    the classic retinitis pigmentosa clinical phenotype.
  cell_types:
  - preferred_term: Retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: Retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:15659613
    reference_title: "Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In primary retinal cell cultures, expression of the mutant PRPF31 proteins reduced rhodopsin expression and caused apoptosis of rhodopsin-positive retinal cells."
    explanation: >
      Direct experimental demonstration that mutant PRPF31 expression reduces
      rhodopsin and causes apoptosis of rhodopsin-expressing retinal cells.
phenotypes:
- name: Night blindness
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: >
    Night blindness is typically the earliest presenting symptom, with median
    age of onset ranging from 8-12 years for nonsense/frameshift/indel
    variants to around 27 years for missense or in-frame variants.
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:32014492
    reference_title: "Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age of onset of first symptoms (usually night-blindness) is lowest in patients with nonsense, frameshift or indel variants, with median age of onset between 8 and 12 years of age."
    explanation: >
      Establishes night blindness as the usual first symptom, with age of
      onset varying significantly by variant class.
- name: Progressive peripheral visual field loss
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: >
    Progressive rod-cone degeneration constricts the peripheral visual field,
    often the reason patients are diagnosed with RP.
  phenotype_term:
    preferred_term: Peripheral visual field constriction
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:32014492
    reference_title: "Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with nonsense, frameshift or splice variants were diagnosed at a median age of 20–30 years (usually because of loss of peripheral vision alongside night blindness)"
    explanation: >
      Confirms peripheral visual field loss, alongside night blindness, as a
      principal driver of clinical diagnosis in PRPF31-RP.
- name: Rod-cone dystrophy
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: >
    PRPF31-RP follows the classic rod-cone dystrophy pattern: rod
    dysfunction and loss predominate, with secondary cone involvement.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:30582903
    reference_title: "Time Course of Disease Progression of PRPF31-mediated Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 6 patients had a non-recordable cone response on their initial visit, suggesting that rod function deteriorates before cone function."
    explanation: >
      Natural-history cohort study directly demonstrates the rod-predominant
      dystrophy pattern: cone responses remained recordable in most patients
      while rod function deteriorated first.
- name: Spicular retinal pigmentation
  category: Ophthalmologic
  frequency: FREQUENT
  description: >
    Bone-spicule-like pigment deposits in the mid-peripheral fundus are a
    classic hallmark of RP-type retinal remodeling.
  phenotype_term:
    preferred_term: Spicular pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:30582903
    reference_title: "Time Course of Disease Progression of PRPF31-mediated Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundus appearance of all affected individuals was consistent with retinitis pigmentosa, with waxy pallor of the optic nerve, retinal vessel attenuation, and bone spicule pigment"
    explanation: >
      Natural-history cohort study directly documents bone-spicule pigment on
      fundus exam in all affected PRPF31 mutation carriers.
- name: Abnormal electroretinogram
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: >
    Rod-predominant ERG abnormalities, ranging from reduced amplitude to
    non-recordable responses, reflect the underlying rod photoreceptor loss.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:30582903
    reference_title: "Time Course of Disease Progression of PRPF31-mediated Retinitis Pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding the rod and cone ERG waveforms, 21 patients had no detectable rod b-wave at their initial visit, while 5 patients had rod b-wave amplitude severely reduced in amplitude."
    explanation: >
      Clinical cohort study directly documents rod-predominant ERG
      abnormality (non-detectable or severely reduced rod b-wave) in
      affected PRPF31 mutation carriers.
genetic:
- name: PRPF31
  gene_term:
    preferred_term: PRPF31
    term:
      id: hgnc:15446
      label: PRPF31
  relationship_type: CAUSATIVE
  notes: >
    PRPF31 (pre-mRNA processing factor 31) encodes a U4/U6.U5 tri-snRNP
    spliceosomal component. It is the second most common genetic cause of
    autosomal dominant retinitis pigmentosa in most populations studied.
  case_fractions:
  - population: United States cohort
    case_fraction_percent: 6.0
    notes: >-
      One of several population-specific case-fraction estimates reported;
      figures range 6-11.1% across US, European, and Chinese cohorts. Likely
      an underestimate given the well-documented non-penetrance of RP11.
    evidence:
    - reference: PMID:32014492
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "they are the second most common genetic cause of adRP in most populations, accounting for 6% of US cases (Sullivan et al., 2013)"
      explanation: Quantifies PRPF31's share of adRP cases in a US cohort.
  evidence:
  - reference: PMID:11545739
    reference_title: "A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report mutations in a gene (PRPF31) homologous to Saccharomyces cerevisiae pre-mRNA splicing gene PRP31 in families with autosomal dominant retinitis pigmentosa linked to chromosome 19q13.4 (RP11; MIM 600138)."
    explanation: >
      Original identification of PRPF31 as the RP11 disease gene.
- name: CNOT3
  gene_term:
    preferred_term: CNOT3
    term:
      id: hgnc:7879
      label: CNOT3
  relationship_type: MODIFIER
  notes: >
    CNOT3 encodes a subunit of the CCR4-NOT transcription complex that
    transcriptionally represses the PRPF31 promoter. Its expression level is
    the principal determinant of penetrance in PRPF31 mutation carriers.
  evidence:
  - reference: PMID:23144630
    reference_title: "CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression"
    explanation: >
      Identifies CNOT3 as the primary trans-acting modifier of PRPF31-RP
      penetrance.
treatments:
- name: PRPF31 Gene Augmentation Therapy
  description: >
    Investigational AAV-mediated gene augmentation, delivering a wild-type
    copy of PRPF31, is under active preclinical investigation as a
    mutation-independent approach exploiting the haploinsufficiency
    mechanism of disease.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:35974011
    reference_title: "Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The rescue of RPE and photoreceptor defective phenotypes by PRPF31 gene augmentation provide the proof of concept"
    explanation: >
      Demonstrates proof-of-concept rescue of both RPE and photoreceptor
      defective phenotypes by AAV-mediated PRPF31 gene augmentation in
      patient-derived organoid models.
- name: Genetic Counseling
  description: >
    Genetic counseling is particularly important in PRPF31-RP given its
    incomplete penetrance -- asymptomatic obligate carriers can still
    transmit disease to offspring, complicating risk assessment and
    segregation analysis.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Low Vision Rehabilitation
  description: >
    Supportive low-vision aids and rehabilitation; no approved
    disease-modifying therapy is currently available for PRPF31-related
    retinopathy.
  treatment_term:
    preferred_term: low vision rehabilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
discussions:
- discussion_id: gap_prpf31_photoreceptor_vs_rpe_primary_site
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Pre-mRNA Splicing of Photoreceptor Genes
  prompt: >-
    Are photoreceptors or the retinal pigment epithelium the primary
    cell type affected by PRPF31 haploinsufficiency?
  rationale: >-
    PRPF31 is ubiquitously expressed and its core splicing function is not
    retina-specific, yet disease is confined to the retina. Some studies
    report retina-enriched PRPF31 expression while others find no tissue
    enrichment, and separate lines of evidence implicate the retinal pigment
    epithelium rather than photoreceptors as the primary affected tissue.
    Resolving this is important for interpreting model systems and designing
    cell-type-appropriate gene therapy delivery.
  evidence:
  - reference: PMID:32014492
    reference_title: "Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It remains unclear whether the photoreceptor cells are the primary affected cells in RP associated with PRPF31, with a number of studies suggesting that the RPE is the primary affected tissue"
    explanation: >
      States the open question directly: whether photoreceptors or RPE are
      the primary PRPF31-RP-affected cell type remains unresolved.
references:
- reference: PMID:11545739
  title: "A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11)."
- reference: PMID:15659613
  title: "Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells."
- reference: PMID:18431455
  title: "Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31."
- reference: PMID:23144630
  title: "CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance."
- reference: PMID:26853529
  title: "Variant haploinsufficiency and phenotypic non-penetrance in PRPF31-associated retinitis pigmentosa."
- reference: PMID:32014492
  title: "Mutation spectrum of PRPF31, genotype-phenotype correlation in retinitis pigmentosa, and opportunities for therapy."
- reference: PMID:30582903
  title: "Time Course of Disease Progression of PRPF31-mediated Retinitis Pigmentosa."
- reference: PMID:35974011
  title: "Modeling PRPF31 retinitis pigmentosa using retinal pigment epithelium and organoids combined with gene augmentation rescue."

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References & Deep Research

References

8

PMID:11545739

A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11).