SNRNP200-Related Dominant Retinopathy (RP33): Research Report

Scope and verification status. I could reach PubMed search listings, a Frontiers full-text page, and web-search summaries. PubMed abstract pages returned 429 or cookie walls. A script to pull abstracts from Europe PMC needed an approval that did not come through, so I did not run it. Consequences: - PMIDs below come from a PubMed result list (title, first author, journal, year). That list shows titles only, so PMIDs are reliable but content descriptions of papers I did not open are inferred from titles. - The only verbatim quote I confirmed is one sentence from Zhang 2021 (Section 3). Everything else is paraphrase and is marked as such. - Items marked [unverified] need checking before they go into the KB. Run just fetch-reference PMID:… and copy exact snippets from the cache.

0. Identifier discrepancy to resolve first

• The template gives MONDO:0800098. I could not confirm it.
• Searches (MedGen, DrugMap, Monarch/MGI mirrors) returned MONDO:0012477 with OMIM:610359. These are for "retinitis pigmentosa 33" (RP33), defined as retinitis pigmentosa caused by mutation in SNRNP200. MGI OMIM:610359, LOVD RP33, MedGen
• Look up both CURIEs with runoak before binding. If MONDO:0800098 is a gene-defined "SNRNP200-related" umbrella term, check the lump/split and mappings.mondo_mappings predicate (exactMatch or narrowMatch only retire the stub).
• I found no Orphanet ORPHA code. Gene OMIM is 601664. OMIM 601664

1. Disease information

• Overview. RP33 is nonsyndromic autosomal dominant retinitis pigmentosa (adRP). It is a rod-cone degeneration caused by heterozygous missense variants in SNRNP200 (2q11.2).
• Gene function. SNRNP200 encodes BRR2 (Brr2), a DEXH-box RNA helicase in the U5 snRNP and the U4/U6-U5 tri-snRNP. It unwinds the U4/U6 duplex to activate the spliceosome. GeneCards
• Discovery. Zhao et al. 2009 (Am J Hum Genet, PMID:19878916) mapped RP33 to 2cen-q12.1. They found c.3260C>T (p.S1087L), segregating through four generations and absent in 400 controls (from search summary AJHG 2009 abstract mirror). The title, from PubMed, describes a mutation affecting U4/U6 unwinding.
• Synonyms. RP33; retinitis pigmentosa 33; SNRNP200-related retinitis pigmentosa; BRR2/ASCC3L1-associated adRP (the older gene name ASCC3L1 appears in Li 2010, PMID:19710410).
• Data type. Aggregated disease-level resources (OMIM, MONDO, ClinVar) plus family and cohort reports.
• Related spliceosomal adRP. PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200 form a "splicing-factor RP" group. See reviews PMID:34395430 (Yang 2021) and PMID:27302685 (Růžičková 2017), and the GeneReviews overview PMID:20301590. This group is a candidate for a Grouping entry, not for lumping.

2. Etiology

• Cause. Monogenic, germline, dominant. No environmental cause is known.
• Genetic risk. Pathogenic or likely pathogenic missense variants in SNRNP200. Modifier genes are not established [unverified].
• Environmental, protective and gene-environment factors. None reported in my searches.
• Recessive alleles. Gerth-Kahlert 2019 (PMID:31260034, title: "Recessive and dominant SNRNP200 variants causing RP") suggests some alleles act recessively. Read this paper before deciding whether the entry needs a recessive subtype.

3. Phenotypes

Clinical features. The terms below are suggested from MedGen's HPO listing for RP33 and from general adRP knowledge. Percentages, onset and severity are not extracted. Frequency data would come from PMID:31486839 (Yusuf 2019, JAMA Ophthalmol, "Clinical characterization of RP with SNRNP200 variants"), which I did not read.

All HPO CURIEs are from memory and must be looked up before use.

• Onset. In the one family I could read (Zhang 2021, PMID:33553197, Front Med), night-vision symptoms began at ages 5, 7 and 9. Children's onset is therefore possible.
• Severity. Reports suggest a severe, early-onset adRP spectrum [unverified].
• Quote (verified from the Frontiers page): "Heterozygous SNRNP200c.C6088T (p.Arg2030Cys) mutation was ascertained in two members of this family." Frontiers
• Family detail from the same page. The variant was in the proband (27) and his father (48). A third affected relative (III-2) lacked the variant, suggesting a phenocopy or a second cause. This weakens simple segregation for p.R2030C.
• Quality of life. I found no data.

4. Genetic and molecular information

• Gene. SNRNP200 (HGNC symbol; KB form hgnc:30[unverified, look up]), OMIM 601664, 2q11.2.
• Variants (confirmed in search summaries):
• c.3260C>T, p.S1087L: the original and recurrent hotspot. See Chen 2013 (PMID:24499697), whose title names the p.S1087L hotspot.
• c.3269G>T, p.R1090L: reported in a 4-generation Chinese family (Li 2010, PMID:19710410, per the OMIM summary).
• p.R2030C (Zhang 2021, PMID:33553197).
• Other variant papers (content inferred from titles only):
• Benaglio 2011, PMID:21618346 (pooled sequencing, new SNRNP200 mutations).
• Liu 2012, PMID:23029027 (novel missense in a Chinese family).
• Zhang 2013, PMID:23887765 (southern Chinese cohort).
• Bowne 2013, PMID:24319334, titled "SNRNP200 causes 1.6% of adRP" (a Mol Vis cohort study).
• Pan 2014, PMID:24940031.
• Coussa 2015, PMID:26720483 (French Canadian).
• Van Cauwenbergh 2017, PMID:28076437 (Belgian).
• Ezquerra-Inchausti 2017, PMID:28045043 (Spanish).
• Wu 2018, PMID:30360737.
• Xiao 2021, PMID:33598457 (138 Chinese adRP families).
• Lee 2023, PMID:36856324.
• Finnegan 2026, PMID:42405195 (Irish cohort).
• Variant class. Heterozygous missense, clustered in the helicase cassettes. S1087L and R1090L sit in the "ratchet" helix of the first Sec63 domain (search summary). No truncating variants are reported in my sources.
• Allele frequency and ClinVar/ClinGen classification. I did not look these up. Check ClinGen gene-disease validity with just check-gene-validity.
• Functional consequence. Not simple loss of function. Evidence is for impaired U4/U6 unwinding, altered splice-site fidelity and altered RNA binding. A dominant-negative mechanism is proposed on zebrafish evidence (Zhang 2021), and the Zimmann 2025 paper is worded as a partial loss/altered function [unverified]. Use functional_impact_category carefully (e.g. DOMINANT_NEGATIVE only if a source states it).
• Somatic or germline. Germline.
• Epigenetics and chromosomal abnormalities. Not applicable or not reported.

5. Environmental information

Not applicable. No toxins, lifestyle factors or infectious agents are reported as contributors. Separately, SNRNP200 has a role in viral RNA sensing and IRF3 activation (Tremblay 2016, PMID:27454487). That is an immune function of the protein, not an infectious cause of the retinopathy.

6. Mechanism and pathophysiology

Causal chain (steps marked inferred are not directly demonstrated in patient retina):

1. A heterozygous missense variant in SNRNP200 (e.g. S1087L, R1090L) changes the Brr2 helicase. These variants sit in the first Sec63 ratchet region (search summary).
2. The altered Brr2 is still incorporated into the spliceosome. snRNP assembly is not compromised (human-cell study, search summary of PMID:26968627 [PMID from a DisGeNET index entry; verify]).
3. U4/U6 unwinding is impaired. The yeast Brr2p equivalents show marked unwinding defects without assembly defects (search summary of Zhao 2009).
4. The mutant protein changes binding to U4 and U6 snRNAs (iCLIP, FRAP and helicase assays in HeLa and RPE cells, PMC11883072 = Zimmann 2025, PMID:40045025). Mutant Brr2 also spends less time on pre-mRNAs (Cvačková 2014, PMID:24302620, per OMIM summary).
5. Splicing fidelity falls, with more cryptic 5' splice-site use in a β-globin reporter (OMIM summary of Cvačková 2014) and altered splicing of cellular transcripts such as LDHA (NLK record summary).
6. Inferred: the altered splicing of retina-relevant transcripts, together with spliceosome stress in cells with a very high splicing load, causes rod photoreceptor and RPE dysfunction.
7. Rod photoreceptors degenerate, then cones, causing night blindness, field loss and eventual central vision loss.

Open questions. Why a ubiquitous protein harms mainly the retina is unresolved. Tissue-specificity reviews are PMID:40264708 (Kemal 2025) and PMID:27302685. A Brr2–Prp8 interaction is relevant, because the Prp8 C-terminal tail inhibits Brr2 (Mozaffari-Jovin 2013, PMID:23704370), and the Zimmann 2025 title concerns SNRNP200 variants and PRPF8 binding. Mozaffari-Jovin 2014 (PMID:24643059) covers Brr2 regulation and retinal disease.

Suggested ontology terms (look up before use; GO IDs from memory): - GO: mRNA splicing, via spliceosome (GO:0000398); U4/U6 x U5 tri-snRNP complex (GO:0046540); RNA helicase activity (GO:0003724). - CL: retinal rod cell (CL:0000604); retinal pigment epithelial cell (CL:0002586); retinal cone cell (CL:0000573). - No transcriptomic, proteomic or metabolomic patient datasets were found. Zimmann 2025 contains iCLIP data from HeLa and RPE cells.

7. Anatomical structures affected

• Organ. Retina, bilateral; the optic disc is secondarily pale. UBERON suggestions (verify): retina (UBERON:0000966), eye (UBERON:0000970), optic disc (UBERON:0001789).
• Cells. Rod photoreceptors first, then cones; RPE is implicated.
• Subcellular. Nucleus, nuclear speckles and the spliceosome (GO:0005681 spliceosomal complex).
• Extra-retinal. Typically none (nonsyndromic).
• Lateralization. Bilateral; symmetry is not documented in my sources.

8. Temporal development

• Onset. Childhood to young adult (symptoms at 5–9 years in one family). Adult-onset families are also reported for other alleles [unverified].
• Progression. Progressive rod-cone degeneration. Staging and quantification are in Yusuf 2019, PMID:31486839 (unread).
• Remission. None expected.

9. Inheritance and population

• Inheritance. Autosomal dominant (HP:0000006). Penetrance, expressivity and any anticipation were not verified.
• Prevalence of the genetic cause. Bowne 2013 (PMID:24319334): per its title, SNRNP200 accounts for about 1.6% of adRP in that cohort.
• Population distribution. Chinese cohorts report repeated findings, with S1087L a hotspot (PMID:24499697). Other cohorts are listed in Section 4. A founder effect is not established.
• Overall disease prevalence and sex ratio. No data found. Parent group: adRP in total is roughly 1 in 3,500–4,000 for all RP, which I am quoting from general knowledge [unverified].

10. Diagnostics

• Clinical. Fundus exam, optical coherence tomography (OCT), fundus autofluorescence, visual fields and full-field ERG (rod-cone pattern). Retinal imaging details for SNRNP200 patients are in Yusuf 2019 (unread).
• Genetic. Retinal dystrophy gene panels or exome sequencing. SNRNP200 is on the Genomics England PanelApp retinal panels (PanelApp). Copy-number analysis is of marginal use (Bujakowska 2017, PMID:27735924).
• Differential. Other adRP genes (RHO, PRPF31, PRPF8, PRPF3, PRPF6, PRPF4, RP1, PERIPHERIN/PRPH2, IMPDH1). The GeneReviews overview PMID:20301590 gives the standard approach.
• Screening. Cascade testing of relatives. No newborn screening.

11. Outcome and prognosis

No survival effect (nonsyndromic). Expected outcome is progressive vision loss with legal blindness in many older patients. Complications likely include cataract and cystoid macular edema, as in RP generally [unverified for this gene]. Genotype-specific prognosis is the focus of Yusuf 2019.

12. Treatment

• No disease-modifying therapy for SNRNP200-RP is approved.
• Supportive care. Low-vision rehabilitation, orientation and mobility training, and cataract or macular edema management. Suggested NCIT terms (verify): Supportive Care (NCIT:C15747), Rehabilitation (NCIT:C15315), Genetic Counseling (NCIT:C15240).
• Gene therapy. Not applicable to a dominant-negative or toxic-gain allele in the usual replacement approach. Allele-specific silencing or editing is theoretical. No SNRNP200 trial was found; I did not search ClinicalTrials.gov directly.
• Experimental lead. N-acetylcysteine reduced retinal defects in Drosophila SNRNP200 models (Mayer 2026, PMID:42593897, title only). Treat as preclinical.
• Pharmacogenomics. None.

13. Prevention

Genetic counselling and cascade testing; prenatal or preimplantation diagnosis is possible for a known familial variant. No primary prevention exists.

14. Other species and natural disease

No naturally occurring disease linked to SNRNP200 was found in my searches. I did not check OMIA. Orthologs exist in all model species below (NCBI Gene IDs not looked up).

15. Model organisms

• Zebrafish. snrnp200 is expressed in the retinal ciliary marginal zone. Mutant R2030C mRNA gave deformities in 53% of larvae versus 9% for wild type. Co-injection with morpholino raised mortality, interpreted as dominant-negative (Zhang 2021, PMID:33553197). Caveat: the text and Figure 6 legend disagree on mortality (77% vs 34%), and this is an overexpression model, so fidelity is low. Earlier work on Snrnp200 knockdown in rods is Liu 2015, PMID:26137319.
• Mouse. Graziotto 2011 (PMID:20811066) describes three splicing-factor RP mouse models (title: late-onset degeneration). Per the title these are Prpf3, Prpf8 and Prpf31 models, not Snrnp200, [unverified]. I found no Snrnp200 patient-allele mouse.
• Drosophila. SNRNP200 models (Mayer 2026, PMID:42593897).
• C. elegans. Splicing-related RP mutations modeled (Kukhtar 2020, PMID:31919495).
• Yeast. Brr2p mutants show U4/U6 unwinding defects (see Section 6).
• Human cells and iPSC. HeLa and RPE cells (Zimmann 2025). An iPSC line from an adRP patient exists (Zhang 2025, PMID:40403403, which I have not confirmed carries a SNRNP200 variant).
• Dismech note. Use animal_models for zebrafish, Drosophila and C. elegans, with modeled_mechanisms links. Use experimental_models for cell lines and iPSC. Cell-line splicing data should carry evidence_source: IN_VITRO.

Curation recommendations

1. Verify MONDO:0800098 vs MONDO:0012477 first.
2. Fetch and read PMID:19878916, 31486839, 24319334, 31260034, 24302620, 40045025 before writing evidence; copy snippets from the cache, not from this report.
3. Consider a splicing-factor RP Grouping, and a module for spliceosome function (check just list-modules splic first).
4. Treat the R2030C family as weakly segregating, because of the affected non-carrier.
5. Record the dominant-negative claim as proposed, not established.

Sources

• Zhang 2021, Frontiers in Medicine (full text)
• Zimmann 2025, Cell Mol Life Sci (PMC11883072)
• OMIM 601664
• AJHG 2009 abstract mirror
• MGI OMIM:610359
• LOVD RP33
• MedGen
• PanelApp SNRNP200
• GeneCards SNRNP200
• PubMed result list for "SNRNP200 retinitis pigmentosa" (source of all PMIDs above).

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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:0000662 (1 mention) - the report calls it "Night blindness (nyctalopia)"; HP calls it Nyctalopia, and lists "Night blindness" among its other names
• HP:0000510 (1 mention) - the report calls it "Rod-cone dystrophy / retinitis pigmentosa"; HP calls it Rod-cone dystrophy, and lists "Retinitis pigmentosa" among its other names
• HP:0007737 (1 mention) - the report calls it "Bone-spicule retinal pigmentation"; HP calls it Spicular pigmentation of the retina, and lists "Bone corpuscle fundus pigmentation" among its other names
• GO:0000398 (1 mention) - the report calls it "GO: mRNA splicing, via spliceosome"; GO calls it mRNA splicing, via spliceosome
• CL:0000604 (1 mention) - the report calls it "CL: retinal rod cell"; CL calls it retinal rod cell

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: OMIM.

24 of 25 terms resolved to a current term; the rest could not be looked up either way.