PRPF8-Related Retinopathy

Mendelian MONDO:0700234 Pathograph 11 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy Spliceosomopathy

PRPF8-related retinopathy (retinitis pigmentosa 13, RP13) is an autosomal dominant rod-cone degeneration caused by heterozygous variants in PRPF8, the central scaffold protein of the U5 snRNP and the spliceosome's catalytic core. Variants cluster in the C-terminal Jab1/MPN region that regulates the Brr2 RNA helicase, and most are thought to act through altered helicase regulation rather than simple loss of PRPF8. The result is defective 5' splice-site selection and cryptic splicing that falls mainly on ciliary and retina-specific transcripts, followed by photoreceptor degeneration with night blindness and constricting visual fields. Expressivity varies within families and penetrance is incomplete. PRPF8 accounts for about 2 to 3 percent of autosomal dominant retinitis pigmentosa, and cystoid macular edema is unusually common.

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Mappings

MONDO
MONDO:0010806 retinitis pigmentosa 13 Not Yet Curated
skos:narrowMatch MONDO
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Heterozygous variants with variable expressivity within families and incomplete penetrance, including carriers with near-normal retinas late in life.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:22039234 SUPPORT Human clinical
"This is the first report of marked intrafamilial variability associated with mutations in the PRPF8 gene, including incomplete penetrance."
Documents dominant inheritance with variable expressivity and non-penetrance.
PMID:11468273 SUPPORT Human clinical
"Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree"
Cosegregation of heterozygous PRPF8 variants in dominant RP13 families.
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Discussions and Knowledge Gaps

1
Do PRPF8 variants impair RPE phagocytosis in human cells, as they do in knock-in mice?
HUMAN MODEL MISMATCH OPEN prpf8_rpe_phagocytosis_mouse_vs_human
Attached to
pathophysiology#Retinal Pigment Epithelium Dysfunction
Prpf8 H2309P mice show reduced RPE phagocytosis and loss of its diurnal burst, but patient-derived RPE carrying a PRPF8 missense variant phagocytosed outer segments like wild type. Organoid work shows that photoreceptors degenerate without any RPE, while another patient iPSC-RPE line had barrier and polarity defects. Whether RPE failure is a primary driver in patients, a secondary contributor, or a mouse-specific feature decides which cell a therapy has to reach.
Show evidence (1 reference)
PMID:30572641 SUPPORT In vitro / ex vivo
"These data suggest that patient-derived iPSCs, both diseased and corrected, are able to differentiate into RPE cells with a near normal phenotype and without differences in phagocytosis, a result that differs from previous mouse models."
The authors state the conflict with the mouse model.
⚙

Pathophysiology

5
PRPF8 C-Terminal Variant
Most variants are missense changes clustered in the last exons of PRPF8, in the C-terminal region that regulates the Brr2 helicase; H2309P is the best-characterized allele. Nonsense variants in the same region are also reported and are predicted to escape nonsense-mediated decay. Some alleles outside the last exon, such as T1931M, lower PRPF8 levels in patient RPE, so reduced dosage may contribute for those.
PRPF8 hgnc:17340 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRPF8 (hgnc:17340). hgnc:17340 is a gene from the HUGO Gene Nomenclature Committee.
U5 snRNA binding GO:0030623 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves U5 snRNA binding (GO:0030623). GO:0030623 is a molecular function from the Gene Ontology.
U5 snRNP GO:0005682 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves U5 snRNP (GO:0005682). GO:0005682 is a cellular component from the Gene Ontology.
Downstream
Impaired Regulation of the Brr2 Helicase
Show evidence (3 references)
PMID:11468273 SUPPORT Human clinical
"The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript."
The founding report places all variants in a short C-terminal stretch.
CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z SUPPORT Other
"Nonsense variants have also been associated with disease; it is predicted that C-terminal stop mutations may escape nonsense mediated decay"
ClinGen summary of truncating PRPF8 variants.
PMID:38605034 SUPPORT BACKGROUND Human clinical
"The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13"
Identifies the variant hotspot as the Brr2-regulating region.
Impaired Regulation of the Brr2 Helicase
The PRPF8 C-terminal tail normally inserts into the RNA-binding tunnel of the Brr2 helicase and represses it until U4/U6 unwinding is due. RP13 variants weaken that repression and the PRPF8-Brr2 interaction, disturbing U5 snRNP maturation, spliceosome activation and the transition between the two catalytic steps, and lowering overall splicing efficiency.
Brr2-driven U4/U6 release during spliceosome activation GO:0000388 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Brr2-driven U4/U6 release during spliceosome activation, annotated with spliceosome conformational change to release U4 (or U4atac) and U1 (or U11) (GO:0000388). GO:0000388 is a biological process from the Gene Ontology.
Downstream
Altered 5' Splice-Site Selection in Ciliary and Retinal Transcripts
Show evidence (3 references)
PMID:23704370 SUPPORT In vitro / ex vivo
"Inefficient Brr2 repression is the only recognizable phenotype associated with certain retinitis pigmentosa-linked Prp8 mutations that map to its C-terminal tail."
Structural and biochemical evidence that RP variants weaken Brr2 repression.
PMID:17934474 SUPPORT Model organism
"RP mutations in Prp8p in yeast result in nuclear accumulation of the precursor U5 snRNP, apparently as a consequence of disrupting the interaction of Prp8p with Brr2p."
In yeast the same variants disrupt the Prp8-Brr2 interaction and U5 snRNP maturation.
PMID:26968627 SUPPORT Model organism
"Though Prp8-RP mutants do not cause defects in splicing fidelity, they result in an overall decrease in splicing efficiency."
Yeast RP mutants lower splicing efficiency rather than fidelity.
Altered 5' Splice-Site Selection in Ciliary and Retinal Transcripts
In patient iPSC-derived retinal cells carrying H2309P, weak 5' splice sites are used less, cryptic splicing increases, and the changes fall mainly on ciliary and retina-specific transcripts. Other RP13 variants reduce PRPF8 binding to pre-mRNA and slow intron removal in RPE cells.
mRNA 5'-splice site recognition GO:0000395 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mRNA 5'-splice site recognition (GO:0000395). GO:0000395 is a biological process from the Gene Ontology.
Downstream
Photoreceptor Ciliary Defects and Rod Degeneration
Retinal Pigment Epithelium Dysfunction
Show evidence (2 references)
PMID:38605034 SUPPORT In vitro / ex vivo
"for which disruption impaired alternative splicing and weak/suboptimal 5'SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts"
The splicing defect in patient-derived cells and the transcripts it targets.
PMID:40045025 SUPPORT In vitro / ex vivo
"The RP variants of PRPF8 did not affect snRNAs, but showed a reduced binding to pre-mRNAs, which resulted in the slower splicing of introns and altered expression of hundreds of genes in RPE cells."
A second route by which RP13 variants alter splicing in retinal cells.
Photoreceptor Ciliary Defects and Rod Degeneration
Photoreceptors show ciliary and polarity defects and outer segment thinning, and rods are lost before cones. In retinal organoids these defects arise in the neural retina without RPE, so they are not only secondary to RPE failure. The cilium assembly binding is inferred from the reported ciliary defects; the sources do not show which step of ciliogenesis fails.
rod photoreceptor CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves rod photoreceptor, annotated with retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology. cone photoreceptor CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cone photoreceptor, annotated with retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
photoreceptor cilium assembly GO:0060271 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal photoreceptor cilium assembly, annotated with cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology.
Downstream
Night blindness
Constriction of peripheral visual field
Rod-cone dystrophy
Abnormal electroretinogram
Show evidence (3 references)
PMID:38605034 SUPPORT In vitro / ex vivo
"We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects."
Photoreceptor loss and ciliary defects in patient-derived retinal cells.
PMID:41731009 SUPPORT In vitro / ex vivo
"Together, we present a model of RP that recapitulates photoreceptor degeneration and demonstrates that these defects are independent of RPE degeneration."
Photoreceptor degeneration in organoids lacking RPE.
PMID:15126168 SUPPORT Human clinical
"All eyes showed loss of rod photoreceptors."
Rod loss in post-mortem eyes. The finding pools one PRPF8 Arg2310Gly eye with three rhodopsin-RP eyes, so it is not specific to PRPF8.
Retinal Pigment Epithelium Dysfunction
Patient iPSC-derived RPE carrying a PRPF8 variant shows weakened barrier function, disrupted polarity, loss of apical microvilli and pigment granules, and splicing changes enriched in cilium and melanosome pathways, all reversed by base-editing correction. In Prpf8 H2309P knock-in mice, primary RPE from homozygous animals phagocytoses less at a young age, and heterozygous RPE degenerates morphologically by two years. Another patient iPSC-RPE line phagocytosed normally, so how much RPE failure contributes in patients is unresolved.
retinal pigment epithelial cell CL:0002586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal pigment epithelial cell (CL:0002586). CL:0002586 is a cell type from the Cell Ontology.
Animal models
Prpf8 H2309P knock-in mouse Mouse partially recapitulates Carries the most common human RP13 allele in the endogenous gene and develops late RPE degeneration and reduced RPE phagocytosis.
Show evidence (4 references)
PMID:41533919 SUPPORT In vitro / ex vivo
"PRPF8-mutant RPE cells exhibited decreased PRPF8 mRNA and protein levels, weakened barrier function, and disrupted cell polarity."
RPE defects in patient-derived and engineered PRPF8-mutant cells.
PMID:20811066 SUPPORT Model organism
"The RPE cells of heterozygous Prpf3(+/T494M) and Prpf8(+/H2309P) knockin mice exhibited loss of the basal infoldings and vacuolization"
RPE degeneration in heterozygous Prpf8 knock-in mice, reported at two years of age.
PMID:25111227 SUPPORT Model organism
"In all three mutant models, 37% to 48% decrease in phagocytosis was observed"
Reduced RPE phagocytosis, pooled across homozygous Prpf3, homozygous Prpf8 H2309P and Prpf31 heterozygous mice.
+ 1 more reference
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PRPF8-Related Retinopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Night blindness VERY_FREQUENT Ophthalmological HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night blindness, annotated with Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22039234 SUPPORT Human clinical
"All affected members complained of nyctalopia with variable age of onset."
Nyctalopia in all affected members of two families.
CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z SUPPORT Other
"characterized by classic presentation of night blindness and constriction of visual fields in multiple large families"
ClinGen summary of the presentation across families.
Constriction of peripheral visual field Ophthalmological HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constricted visual fields, annotated with Constriction of peripheral visual field (HP:0001133). HP:0001133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11910553 SUPPORT Human clinical
"a diffuse loss of rod and cone sensitivity, and constricted visual fields (type I)"
Constricted fields in a Dutch RP13 family.
Rod-cone dystrophy Ophthalmological HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:11910553 SUPPORT Human clinical
"a diffuse loss of rod and cone sensitivity"
Combined rod and cone involvement.
PMID:22039234 SUPPORT Human clinical
"ranging from severe rod-cone dystrophy to a 67-year-old patient with a normal retinal appearance and mild rod dysfunction on scotopic electroretinography (ERG)"
Rod-cone dystrophy with a wide severity range within one family.
Abnormal electroretinogram Ophthalmological HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced scotopic ERG responses, annotated with Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22039234 SUPPORT Human clinical
"mild rod dysfunction on scotopic electroretinography (ERG)"
Rod dysfunction on ERG even in the mildest carrier.
Cystoid macular edema FREQUENT Ophthalmological HP:0011505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cystoid macular edema (HP:0011505). HP:0011505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40900079 SUPPORT Human clinical
"we found the highest prevalence of CME in patients with autosomal dominant RP forms due to variants in RHO (58.2%), PRPF8 (72.7%), and PRPF3 (75.0%)"
CME developed in 72.7% of PRPF8 patients in a 580-patient RP cohort.
🧬

Genetic Associations

1
PRPF8 (Causative heterozygous missense variants, clustered in the C-terminal Brr2-regulating region.)
Gene: PRPF8 hgnc:17340 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRPF8 (hgnc:17340). hgnc:17340 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:11468273 SUPPORT Human clinical
"we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families"
Founding gene-disease report.
CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z SUPPORT Other
"PRPF8 | HGNC:17340 | PRPF8-related retinopathy | MONDO:0700234 | AD | Definitive"
ClinGen Definitive classification for this disease.
💊

Medical Actions

1
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for a dominant disorder with incomplete penetrance, where an unaffected carrier can still transmit the variant.
🐁

Animal Models

1
Prpf8 H2309P knock-in mouse
Species
Mouse
Genotype
Prpf8(+/H2309P) and Prpf8(H2309P/H2309P)
Publication
PMID:20811066
Pathograph links
Retinal Pigment Epithelium Dysfunction partially recapitulates fidelity: low observes: cellular Carries the most common human RP13 allele in the endogenous gene and develops late RPE degeneration and reduced RPE phagocytosis.
Limitations: The early phagocytosis defect was measured in homozygous mice, and heterozygotes, the human genotype, show only late RPE morphological change at about two years. The mouse does not develop the photoreceptor degeneration that defines the human disease, and patient iPSC-RPE did not reproduce its phagocytosis defect.
Show evidence (1 reference)
PMID:25111227 SUPPORT Model organism
"we investigated its phagocytic function in Prpf3(T494M/T494M), Prpf8(H2309P/H2309P), and Prpf31(+/-) mice"
Identifies the homozygous Prpf8 knock-in as one of the three models in which the pooled phagocytosis defect was measured.
{ }

Source YAML

click to show 
name: PRPF8-Related Retinopathy
creation_date: "2026-10-25T00:00:00Z"
category: Mendelian
description: >-
  PRPF8-related retinopathy (retinitis pigmentosa 13, RP13) is an autosomal
  dominant rod-cone degeneration caused by heterozygous variants in PRPF8, the central scaffold protein of the U5 snRNP and the spliceosome's
  catalytic core. Variants cluster in the C-terminal Jab1/MPN region that
  regulates the Brr2 RNA helicase, and most are thought to act through
  altered helicase regulation rather than simple loss of PRPF8. The result is defective 5'
  splice-site selection and cryptic splicing that falls mainly on ciliary and
  retina-specific transcripts, followed by photoreceptor degeneration with
  night blindness and constricting visual fields. Expressivity varies within
  families and penetrance is incomplete. PRPF8 accounts for about 2 to 3
  percent of autosomal dominant retinitis pigmentosa, and cystoid macular
  edema is unusually common.
disease_term:
  preferred_term: PRPF8-related retinopathy
  term:
    id: MONDO:0700234
    label: PRPF8-related retinopathy
synonyms:
- Retinitis pigmentosa 13
- RP13
- PRPF8 retinitis pigmentosa
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
- Spliceosomopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010806
      label: retinitis pigmentosa 13
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    notes: >-
      Retinitis pigmentosa 13 is the classically named clinical entity and the
      only MONDO child of the PRPF8 gene-series term used as this entry's
      disease_term.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous variants with variable expressivity within families and
    incomplete penetrance, including carriers with near-normal retinas late in
    life.
  evidence:
  - reference: PMID:22039234
    reference_title: "Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report of marked intrafamilial variability associated with mutations in the PRPF8 gene, including incomplete penetrance."
    explanation: Documents dominant inheritance with variable expressivity and non-penetrance.
  - reference: PMID:11468273
    reference_title: "Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree"
    explanation: Cosegregation of heterozygous PRPF8 variants in dominant RP13 families.
pathophysiology:
- name: PRPF8 C-Terminal Variant
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    Most variants are missense changes clustered in the last exons of PRPF8,
    in the C-terminal region that regulates the Brr2 helicase; H2309P is the
    best-characterized allele. Nonsense variants in the same region are also
    reported and are predicted to escape nonsense-mediated decay. Some alleles
    outside the last exon, such as T1931M, lower PRPF8 levels in patient RPE,
    so reduced dosage may contribute for those.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PRPF8
    term:
      id: hgnc:17340
      label: PRPF8
  molecular_functions:
  - preferred_term: U5 snRNA binding
    term:
      id: GO:0030623
      label: U5 snRNA binding
  cellular_components:
  - preferred_term: U5 snRNP
    term:
      id: GO:0005682
      label: U5 snRNP
  evidence:
  - reference: PMID:11468273
    reference_title: "Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript."
    explanation: The founding report places all variants in a short C-terminal stretch.
  - reference: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
    reference_title: "PRPF8 / PRPF8-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nonsense variants have also been associated with disease; it is predicted that C-terminal stop mutations may escape nonsense mediated decay"
    explanation: ClinGen summary of truncating PRPF8 variants.
  - reference: PMID:38605034
    reference_title: "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13"
    explanation: Identifies the variant hotspot as the Brr2-regulating region.
  downstream:
  - target: Impaired Regulation of the Brr2 Helicase
    causal_link_type: DIRECT
- name: Impaired Regulation of the Brr2 Helicase
  description: >-
    The PRPF8 C-terminal tail normally inserts into the RNA-binding tunnel of
    the Brr2 helicase and represses it until U4/U6 unwinding is due. RP13
    variants weaken that repression and the PRPF8-Brr2 interaction, disturbing
    U5 snRNP maturation, spliceosome activation and the transition between the
    two catalytic steps, and lowering overall splicing efficiency.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Brr2-driven U4/U6 release during spliceosome activation
    term:
      id: GO:0000388
      label: spliceosome conformational change to release U4 (or U4atac) and U1 (or U11)
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23704370
    reference_title: "Inhibition of RNA helicase Brr2 by the C-terminal tail of the spliceosomal protein Prp8."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Inefficient Brr2 repression is the only recognizable phenotype associated with certain retinitis pigmentosa-linked Prp8 mutations that map to its C-terminal tail."
    explanation: Structural and biochemical evidence that RP variants weaken Brr2 repression.
  - reference: PMID:17934474
    reference_title: "prp8 mutations that cause human retinitis pigmentosa lead to a U5 snRNP maturation defect in yeast."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RP mutations in Prp8p in yeast result in nuclear accumulation of the precursor U5 snRNP, apparently as a consequence of disrupting the interaction of Prp8p with Brr2p."
    explanation: In yeast the same variants disrupt the Prp8-Brr2 interaction and U5 snRNP maturation.
  - reference: PMID:26968627
    reference_title: "Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Though Prp8-RP mutants do not cause defects in splicing fidelity, they result in an overall decrease in splicing efficiency."
    explanation: Yeast RP mutants lower splicing efficiency rather than fidelity.
  downstream:
  - target: Altered 5' Splice-Site Selection in Ciliary and Retinal Transcripts
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38605034
      reference_title: "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5'-splice site (5'SS) selection by spliceosomes"
      explanation: Links PRPF8-Brr2 regulation to 5' splice-site selection in patient-derived cells.
- name: Altered 5' Splice-Site Selection in Ciliary and Retinal Transcripts
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  description: >-
    In patient iPSC-derived retinal cells carrying H2309P, weak 5' splice sites
    are used less, cryptic splicing increases, and the changes fall mainly on
    ciliary and retina-specific transcripts. Other RP13 variants reduce PRPF8
    binding to pre-mRNA and slow intron removal in RPE cells.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mRNA 5'-splice site recognition
    term:
      id: GO:0000395
      label: mRNA 5'-splice site recognition
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38605034
    reference_title: "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "for which disruption impaired alternative splicing and weak/suboptimal 5'SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts"
    explanation: The splicing defect in patient-derived cells and the transcripts it targets.
  - reference: PMID:40045025
    reference_title: "Retinitis pigmentosa-linked mutations impair the snRNA unwinding activity of SNRNP200 and reduce pre-mRNA binding of PRPF8."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The RP variants of PRPF8 did not affect snRNAs, but showed a reduced binding to pre-mRNAs, which resulted in the slower splicing of introns and altered expression of hundreds of genes in RPE cells."
    explanation: A second route by which RP13 variants alter splicing in retinal cells.
  downstream:
  - target: Photoreceptor Ciliary Defects and Rod Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Retinal Pigment Epithelium Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Photoreceptor Ciliary Defects and Rod Degeneration
  conforms_to: "spliceosome_component_dysfunction#Failure of Splicing-Sensitive Cell Populations"
  description: >-
    Photoreceptors show ciliary and polarity defects and outer segment thinning,
    and rods are lost before cones. In retinal organoids these defects arise in
    the neural retina without RPE, so they are not only secondary to RPE
    failure. The cilium assembly binding is inferred from the reported ciliary
    defects; the sources do not show which step of ciliogenesis fails.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: rod photoreceptor
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: cone photoreceptor
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: photoreceptor cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38605034
    reference_title: "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects."
    explanation: Photoreceptor loss and ciliary defects in patient-derived retinal cells.
  - reference: PMID:41731009
    reference_title: "PRPF8-associated retinitis pigmentosa variant induces human neural retina-autonomous photoreceptor defects."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, we present a model of RP that recapitulates photoreceptor degeneration and demonstrates that these defects are independent of RPE degeneration."
    explanation: Photoreceptor degeneration in organoids lacking RPE.
  - reference: PMID:15126168
    reference_title: "Histologic study of retinitis pigmentosa due to a mutation in the RP13 gene (PRPC8): comparison with rhodopsin Pro23His, Cys110Arg, and Glu181Lys."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All eyes showed loss of rod photoreceptors."
    explanation: >-
      Rod loss in post-mortem eyes. The finding pools one PRPF8 Arg2310Gly
      eye with three rhodopsin-RP eyes, so it is not specific to PRPF8.
  downstream:
  - target: Night blindness
  - target: Constriction of peripheral visual field
  - target: Rod-cone dystrophy
  - target: Abnormal electroretinogram
- name: Retinal Pigment Epithelium Dysfunction
  description: >-
    Patient iPSC-derived RPE carrying a PRPF8 variant shows weakened barrier
    function, disrupted polarity, loss of apical microvilli and pigment
    granules, and splicing changes enriched in cilium and melanosome pathways,
    all reversed by base-editing correction. In Prpf8 H2309P knock-in mice,
    primary RPE from homozygous animals phagocytoses less at a young age, and
    heterozygous RPE degenerates morphologically by two years. Another patient
    iPSC-RPE line phagocytosed normally, so how much RPE failure contributes in patients is
    unresolved.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: retinal pigment epithelial cell
    term:
      id: CL:0002586
      label: retinal pigment epithelial cell
  evidence:
  - reference: PMID:41533919
    reference_title: "PRPF8 Mutation-Induced Defects in Human iPSC-Derived RPE Are Rescued by Adenine Base Editing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PRPF8-mutant RPE cells exhibited decreased PRPF8 mRNA and protein levels, weakened barrier function, and disrupted cell polarity."
    explanation: RPE defects in patient-derived and engineered PRPF8-mutant cells.
  - reference: PMID:20811066
    reference_title: "Three gene-targeted mouse models of RNA splicing factor RP show late-onset RPE and retinal degeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The RPE cells of heterozygous Prpf3(+/T494M) and Prpf8(+/H2309P) knockin mice exhibited loss of the basal infoldings and vacuolization"
    explanation: RPE degeneration in heterozygous Prpf8 knock-in mice, reported at two years of age.
  - reference: PMID:25111227
    reference_title: "Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In all three mutant models, 37% to 48% decrease in phagocytosis was observed"
    explanation: >-
      Reduced RPE phagocytosis, pooled across homozygous Prpf3, homozygous
      Prpf8 H2309P and Prpf31 heterozygous mice.
  - reference: PMID:30572641
    reference_title: "Functional Assessment of Patient-Derived Retinal Pigment Epithelial Cells Edited by CRISPR/Cas9."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Functionally, the RPE cells were able to establish apicobasal polarity and phagocytose photoreceptor outer segments at the same capacity as wild-type cells."
    explanation: >-
      Patient-derived PRPF8-mutant RPE phagocytosed normally, contradicting the
      mouse phagocytosis defect.
phenotypes:
- name: Night blindness
  category: Ophthalmological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:22039234
    reference_title: "Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected members complained of nyctalopia with variable age of onset."
    explanation: Nyctalopia in all affected members of two families.
  - reference: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
    reference_title: "PRPF8 / PRPF8-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by classic presentation of night blindness and constriction of visual fields in multiple large families"
    explanation: ClinGen summary of the presentation across families.
- name: Constriction of peripheral visual field
  category: Ophthalmological
  phenotype_term:
    preferred_term: Constricted visual fields
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:11910553
    reference_title: "Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a diffuse loss of rod and cone sensitivity, and constricted visual fields (type I)"
    explanation: Constricted fields in a Dutch RP13 family.
- name: Rod-cone dystrophy
  category: Ophthalmological
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:11910553
    reference_title: "Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a diffuse loss of rod and cone sensitivity"
    explanation: Combined rod and cone involvement.
  - reference: PMID:22039234
    reference_title: "Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ranging from severe rod-cone dystrophy to a 67-year-old patient with a normal retinal appearance and mild rod dysfunction on scotopic electroretinography (ERG)"
    explanation: Rod-cone dystrophy with a wide severity range within one family.
- name: Abnormal electroretinogram
  category: Ophthalmological
  phenotype_term:
    preferred_term: Reduced scotopic ERG responses
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:22039234
    reference_title: "Autosomal dominant retinitis pigmentosa with intrafamilial variability and incomplete penetrance in two families carrying mutations in PRPF8."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild rod dysfunction on scotopic electroretinography (ERG)"
    explanation: Rod dysfunction on ERG even in the mildest carrier.
- name: Cystoid macular edema
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:40900079
    reference_title: "Cystoid Macular Edema in Non-Syndromic Retinitis Pigmentosa: Associations With Causative Genes in a Large Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found the highest prevalence of CME in patients with autosomal dominant RP forms due to variants in RHO (58.2%), PRPF8 (72.7%), and PRPF3 (75.0%)"
    explanation: CME developed in 72.7% of PRPF8 patients in a 580-patient RP cohort.
genetic:
- name: PRPF8
  gene_term:
    preferred_term: PRPF8
    term:
      id: hgnc:17340
      label: PRPF8
  association: >-
    Causative heterozygous missense variants, clustered in the C-terminal
    Brr2-regulating region.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  case_fractions:
  - population: Autosomal dominant retinitis pigmentosa cases
    case_fraction_low: 2
    case_fraction_high: 3
    notes: ClinGen's estimate of the PRPF8 share of autosomal dominant RP.
    evidence:
    - reference: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
      reference_title: "PRPF8 / PRPF8-related retinopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PRPF8-related retinitis pigmentosa is now estimated to cause 2-3% of cases of autosomal dominant retinitis pigmentosa"
      explanation: ClinGen evidence summary.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
    evidence:
    - reference: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
      reference_title: "PRPF8 / PRPF8-related retinopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PRPF8 | HGNC:17340 | PRPF8-related retinopathy | MONDO:0700234 | AD | Definitive"
      explanation: ClinGen gene-disease validity record classifying this pair as Definitive.
  evidence:
  - reference: PMID:11468273
    reference_title: "Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families"
    explanation: Founding gene-disease report.
  - reference: CGGV:assertion_b9efbbc3-6ce1-4f92-8472-627c2060dd88-2023-04-06T160000.000Z
    reference_title: "PRPF8 / PRPF8-related retinopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRPF8 | HGNC:17340 | PRPF8-related retinopathy | MONDO:0700234 | AD | Definitive"
    explanation: ClinGen Definitive classification for this disease.
animal_models:
- name: Prpf8 H2309P knock-in mouse
  species: Mouse
  genotype: Prpf8(+/H2309P) and Prpf8(H2309P/H2309P)
  publication: PMID:20811066
  modeled_mechanisms:
  - target: Retinal Pigment Epithelium Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Carries the most common human RP13 allele in the endogenous gene and
      develops late RPE degeneration and reduced RPE phagocytosis.
    limitations: >-
      The early phagocytosis defect was measured in homozygous mice, and
      heterozygotes, the human genotype, show only late RPE morphological
      change at about two years. The mouse does not develop the photoreceptor
      degeneration that defines the human disease, and patient iPSC-RPE did not
      reproduce its phagocytosis defect.
    evidence:
    - reference: PMID:25111227
      reference_title: "Mutations in pre-mRNA processing factors 3, 8, and 31 cause dysfunction of the retinal pigment epithelium."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we investigated its phagocytic function in Prpf3(T494M/T494M), Prpf8(H2309P/H2309P), and Prpf31(+/-) mice"
      explanation: >-
        Identifies the homozygous Prpf8 knock-in as one of the three models in
        which the pooled phagocytosis defect was measured.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for a dominant disorder with incomplete penetrance, where an
    unaffected carrier can still transmit the variant.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: prpf8_rpe_phagocytosis_mouse_vs_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Retinal Pigment Epithelium Dysfunction
  prompt: >-
    Do PRPF8 variants impair RPE phagocytosis in human cells, as they do in
    knock-in mice?
  rationale: >-
    Prpf8 H2309P mice show reduced RPE phagocytosis and loss of its diurnal
    burst, but patient-derived RPE carrying a PRPF8 missense variant
    phagocytosed outer segments like wild type. Organoid work shows that
    photoreceptors degenerate without any RPE, while another patient iPSC-RPE
    line had barrier and polarity defects. Whether RPE failure is a primary
    driver in patients, a secondary contributor, or a mouse-specific feature
    decides which cell a therapy has to reach.
  evidence:
  - reference: PMID:30572641
    reference_title: "Functional Assessment of Patient-Derived Retinal Pigment Epithelial Cells Edited by CRISPR/Cas9."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that patient-derived iPSCs, both diseased and corrected, are able to differentiate into RPE cells with a near normal phenotype and without differences in phagocytosis, a result that differs from previous mouse models."
    explanation: The authors state the conflict with the mouse model.
references:
- reference: PMID:11468273
  title: "Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13)."
- reference: PMID:38605034
  title: "PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects."
notes: >-
  A single patient with autosomal recessive retinitis pigmentosa and a PRPF8
  variant has been studied in iPSC-derived RPE (PMID:33994920); this entry
  covers the dominant disease, and that report is not used here. ClinGen
  excludes non-retinal PRPF8 associations (glaucoma, myeloid leukemia) from
  this disease, and so does this entry. No GeneReviews chapter is specific to
  PRPF8; the nonsyndromic retinitis pigmentosa overview covers it among other
  genes.
📚

References & Deep Research

References

2
PMID:11468273
Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).
No top-level findings curated for this source.
PMID:38605034
PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸
PRPF8-Related Retinopathy (RP13): research report
claude-haiku-5-5, claude-sonnet-5-5 10 citations 2026-10-25T16:36:52.714116

PRPF8-Related Retinopathy (RP13): research report

Scope and verification. I ran three web searches. This report relies on what they returned: the Atkinson 2024 and Arzalluz-Luque 2021 papers, the 2018 CRISPR iPSC-RPE paper, the OMIM #600059 synopsis, and the PanelApp and GenCC listings. I did not open full texts. I give PMC or URL links instead of PMIDs where I couldn't confirm the PMID. Anything marked [unverified] is background knowledge that this session's searches did not confirm. Run just fetch-reference and just preflight-dr before any of it goes into the KB. Most of the PRPF8 literature on penetrance, frequency, and variant spectrum (for example McKie 2001, Towns 2010, Maubaret 2011) was not retrieved. I did not look for ClinGen, Orphanet, ClinicalTrials.gov, gnomAD or ClinVar records.

1. Disease information

  • Overview. PRPF8-related retinopathy is autosomal dominant retinitis pigmentosa 13 (RP13). It is non-syndromic rod-cone degeneration caused by heterozygous variants in PRPF8. The PRPF8 protein is a core scaffold of the U5 snRNP and spliceosome. The OMIM #600059 synopsis lists night blindness, retinal degeneration, bone-spicule pigment clumping, attenuated vessels, a pale optic disc, constricted visual fields, and in some patients subcapsular cataract and cystoid macular edema. (OMIM #600059 mirror, FindZebra)
  • Identifiers.
  • OMIM phenotype 600059 (RP13); gene OMIM 607300; locus 17p13.3.
  • MedGen UID 325486 cross-references OMIM 600059 (MedGen).
  • MONDO:0700234 comes from the task template, not from my searches.
  • Orphanet code, ICD-10/11 and MeSH: not found. Look up the Orphanet code (likely under the "retinitis pigmentosa" ORPHA:791 family) before use.
  • Synonyms. RP13; retinitis pigmentosa 13; PRPF8-associated retinitis pigmentosa; RP13-PRPF8; spliceosomal (PRPF-associated) retinitis pigmentosa.
  • Data source. The OMIM and PanelApp content is aggregated disease-level information. The iPSC studies come from individual patients (H2309P).

2. Etiology

  • Causal factor. Heterozygous PRPF8 variants, clustered in the C-terminal region (exon 42; the Brr2-regulating Jab1/MPN domain region). PanelApp reports that variants typically cluster in exon 42, with variable expressivity and incomplete penetrance (PanelApp).
  • Hotspot. The Atkinson 2024 study states that the PRPF8 carboxy-terminus, which regulates the RNA helicase Brr2, is a hotspot for RP13 mutations (Nat Commun 2024, PMC11009313).
  • Number of mutations. More than 20 RP-associated PRPF8 mutations have been reported in patients (Drosophila RP13 model, DMM 2020, via search result).
  • Risk, protective and environmental factors. None established in the sources found. Modifier alleles and gene-environment interactions are not documented, so I would record them as not available. Incomplete penetrance implies unidentified modifiers.
  • Separate association. PanelApp lists a less established PRPF8 association with a developmental disorder and intellectual disability, with some variants possibly non-pathogenic. This is probably a distinct entity and should not be merged into this entry.

3. Phenotypes

Frequencies are not quantified in the retrieved sources. HP IDs are suggestions and must be looked up before binding.

Phenotype Suggested HPO Notes
Night blindness HP:0000662 Onset from early childhood to the mid-thirties (OMIM). In a South African kindred, first symptoms appeared at ages 4–10 (FindZebra).
Rod-cone dystrophy / retinal degeneration HP:0000510 (rod-cone dystrophy), HP:0000546 (retinal degeneration) Severity varies from severe to near-normal retinal appearance in British families.
Bone-spicule pigmentation HP:0007737
Attenuated retinal vessels HP:0000501
Pale optic disc HP:0000543
Constricted visual fields HP:0001133
Cataract (subcapsular) HP:0000518 Present in some patients.
Cystoid macular edema HP:0011505 Present in some patients.
  • Severity and course. An Italian P2301S family had a milder course with partly preserved cone function (IRIS-CNR). Severity is variable and penetrance is incomplete.
  • Quality of life. No data found.

4. Genetic and molecular information

  • Gene. PRPF8 (hgnc:17340 [unverified; confirm in HGNC]), 17p13.3.
  • Variant class. Mostly missense or in-frame changes in the C-terminal domain, not null alleles. Examples are H2309P, which is the best-characterised, and P2301S in the Italian family.
  • Functional consequence.
  • The mechanism is not simple haploinsufficiency.
  • In the patient iPSC model (H2309P), the authors link PRPF8/Brr2 dysregulation to impaired 5′ splice-site selection: weak or suboptimal 5′SS selection and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. They also report altered spliceosome kinetics (Atkinson 2024).
  • In Drosophila, the pathogenicity of RP-Prp8 mutations correlated with the severity of the equivalent human clinical phenotypes.
  • Whether the effect is a loss of function, a dominant negative, or a hypomorphic mechanism is not settled in the sources found.
  • Origin. Germline.
  • Modifiers, epigenetics, chromosomal changes. None documented.
  • Related genes. PRPF3, PRPF4, PRPF6, PRPF31 and SNRNP200 cause similar spliceosomal RP. This is the basis for a possible grouping.
  • Population frequency and ClinVar/ClinGen classification. Not retrieved. Check ClinVar, gnomAD and the GenCC record (GenCC submission) before assigning any gene_disease_validity.

5. Environmental information

No environmental, lifestyle or infectious factors are documented. Leave these sections absent.

6. Mechanism / pathophysiology

Causal chain. Steps marked (inferred) are not directly demonstrated in the sources.

  1. A heterozygous C-terminal PRPF8 variant (such as H2309P) alters the Brr2-regulating region of PRPF8 (demonstrated structurally and in cells).
  2. This dysregulates the Brr2 helicase, which changes spliceosome kinetics and 5′ splice-site selection (Atkinson 2024).
  3. The altered selection causes weak-site use and enhanced cryptic splicing. The effects are enriched in ciliary and retinal-specific transcripts, so a retina-specific splicing program is disproportionately affected (Atkinson 2024; Arzalluz-Luque 2021).
  4. In patient iPSC-derived RPE, there are widespread splicing changes in spliceosome components, with global changes in splice-site selection and exon inclusion (Frontiers Neurosci 2021, PMC8116631).
  5. In retinal organoids, the phenotype includes photoreceptor loss, apical-basal polarity defects and ciliary defects (Atkinson 2024).
  6. Progressive rod loss followed by cone loss produces night blindness, field constriction and the fundus changes (inferred from the clinical course).
  7. Branch, RPE phagocytosis (disputed).
  8. Prpf8 H2309P/H2309P mouse RPE shows reduced phagocytosis and loss of its diurnal rhythm.
  9. Patient iPSC-RPE phagocytosed outer segments at wild-type capacity and established apicobasal polarity (PMC6321630).
  10. Whether RPE dysfunction contributes in humans is therefore unresolved. Record this as a HUMAN_MODEL_MISMATCH discussion.
  11. Open question: why the retina. PRPF8 is ubiquitous, so the retina-restricted phenotype remains unexplained. Proposed explanations are retina-specific splicing programs and the high splicing demand of photoreceptors. These are hypotheses.

Suggested terms (look up before binding): GO mRNA splicing, via spliceosome (GO:0000398); U5 snRNP; cilium organization; CL rod photoreceptor cell (CL:0000604); retinal pigment epithelial cell (CL:0002586). Unlike many retinal conditions, there is no immune or metabolic arm.

7. Anatomical structures affected

  • Organ and tissue. Retina (UBERON:0000966) in both eyes, mainly the rod photoreceptor layer and the RPE. The lens is secondarily affected (cataract).
  • Subcellular. The nucleus and spliceosome (U5 snRNP); the photoreceptor connecting cilium.
  • Laterality. Bilateral.

8. Temporal development

  • Onset. Childhood to the mid-thirties, which is variable. The age of onset in the South African kindred was 4–10 years.
  • Progression. Progressive rod-cone degeneration with a variable rate. Some carriers remain nearly normal because of incomplete penetrance.
  • Duration. Lifelong. No remission is described.

9. Inheritance and population

  • Inheritance. Autosomal dominant (HP:0000006), with incomplete penetrance and variable expressivity (OMIM; two British families showed marked intrafamilial variability).
  • Prevalence. Not found. Do not enter a rate. The broader RP prevalence is roughly 1 in 4,000 [unverified]. PRPF8 accounts for only a small share of adRP [unverified].
  • Founder effects, sex ratio, anticipation, mosaicism. Not documented here. Family reports come from South Africa, the UK and Italy.

10. Diagnostics

  • Clinical. Fundus examination, visual field testing, full-field ERG (rod-dominant reduction), OCT (ellipsoid-zone loss, macular edema) and autofluorescence.
  • Genetic. An inherited retinal disease gene panel or exome sequencing that includes PRPF8 exon 42. Check that the panel covers the C-terminal exons. Interpret VUS cautiously, since PanelApp notes some variants may not be pathogenic.
  • Differential. Other adRP genes, especially the other spliceosomal genes (PRPF31, PRPF3, SNRNP200, PRPF6, PRPF4) and rhodopsin (RHO) RP.
  • GeneReviews. Not checked. Run just check-genereviews for this entry.

11. Outcome and prognosis

Not quantified in the retrieved sources. Expect gradual loss of peripheral vision and, in severe families, eventual loss of central vision. Complications are cataract and cystoid macular edema. Severity within families is variable, so prognosis is hard to predict from genotype alone.

12. Treatment

  • Approved disease-modifying therapy. None found for PRPF8. The approved voretigene therapy targets RPE65 and does not apply here.
  • Supportive. Low-vision rehabilitation (NCIT:C15315 Rehabilitation), cataract surgery (NCIT:C15329 Surgical Procedure) and treatment of macular edema with carbonic anhydrase inhibitors [unverified]. Genetic counseling is NCIT:C15240.
  • Experimental. In the mechanistic literature, the main therapeutic lead is gene-supplementation or splicing-correction approaches. A thesis reported PRPF31 supplementation rescuing phagocytosis in PRPF31-linked cells, but that is a different gene. No PRPF8 trial was found, and I did not search ClinicalTrials.gov.

13. Prevention

  • Genetic counseling and cascade testing of relatives.
  • Prenatal or preimplantation testing are options for known familial variants.
  • Incomplete penetrance complicates risk estimates for asymptomatic carriers.
  • No behavioral, environmental or immunization strategies apply.

14. Other species and natural disease

No naturally occurring PRPF8 retinopathy in animals was found. I did not check OMIA. The Drosophila ortholog is Prp8.

15. Model organisms

  • Mouse. Prpf8 H2309P knock-in (homozygous). RPE shows reduced phagocytosis and loss of its diurnal rhythm. I did not retrieve the retinal phenotype. Heterozygous mice, which are the closer genetic match, were not covered. (From the search summary of the iPSC-RPE paper.)
  • Drosophila. RP-Prp8 mutations modeled in flies; the severity of the fly phenotype correlates with the human clinical severity (DMM 2020, Whiterose eprint). This supports a PARTIALLY_RECAPITULATES or RECAPITULATES link with fidelity: MODERATE.
  • Human iPSC models.
  • Patient iPSC-derived RPE (p.H2309P) with CRISPR-corrected isogenic clones (PMC6321630). It shows normal phagocytosis and polarity.
  • iPSC-derived RPE showing widespread splicing changes (PMC8116631).
  • Retinal organoids showing photoreceptor loss, polarity defects and ciliary defects (PMC11009313).
  • Limitations. The mouse and iPSC-RPE phagocytosis findings conflict. Overlapping cell lines may make the iPSC papers non-independent. Organoids lack the full RPE and photoreceptor interface.

Curation notes for dismech

  1. Use inheritance_term HP:0000006 (autosomal dominant) with the incomplete penetrance and variable expressivity noted in the description.
  2. Do not set a gene_disease_validity tier without a ClinGen or GenCC record. The GenCC submission SGC-106261.2 is a lead only; open it and read the classification.
  3. Every PMID must be fetched with just fetch-reference and quoted exactly. This report contains no verified snippets.
  4. Open HUMAN_MODEL_MISMATCH for the RPE phagocytosis conflict and KNOWLEDGE_GAP for the retina-specificity question.
  5. Consider a covering Grouping for spliceosomal (PRPF-associated) RP.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 3
Resolved 3
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 3
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 19
Resolved 18
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 8
Terms named correctly 3
Terms named as a different term 1
Terms whose name is worth a second look 4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0000501 (1 mention) - the report calls it "Attenuated retinal vessels"; HP calls it Glaucoma

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0007737 (1 mention) - the report calls it "Bone-spicule pigmentation"; HP calls it Spicular pigmentation of the retina, and lists "Bone spicule pigmentation of the retina" among its other names
  • HP:0000543 (1 mention) - the report calls it "Pale optic disc"; HP calls it Optic disc pallor, and lists "Pale optic discs" among its other names
  • HP:0000518 (1 mention) - the report calls it "Cataract (subcapsular)"; HP calls it Cataract, and lists "Cataracts" among its other names
  • HP:0000006 (2 mentions) - the report calls it "autosomal dominant"; HP calls it Autosomal dominant inheritance, and lists "Autosomal dominant" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.