🔗

Mappings

MONDO

MONDO:0019200 retinitis pigmentosa Not Yet Curated

This entry is the subset of retinitis pigmentosa caused by dominant variants in RNU4-2 and the RNU6 paralogs, so the whole retinitis pigmentosa class is broader than it. A narrower MONDO class was searched for on 2026-11-01 with the OLS4 search API restricted to MONDO. The query "RNU4-2" returned one class, MONDO:0008871 microcephalic osteodysplastic primordial dwarfism type I, whose definition names RNU4ATAC, not RNU4-2. The queries "RNU6", "RNU6-1", "U4 snRNA", "U6 snRNA" and "snRNA retinitis pigmentosa" returned no classes. The newest numbered classes, retinitis pigmentosa 96 to 101 (exact-label OLS4 search; "retinitis pigmentosa 102" returned nothing), are not this disease: the OLS4 v2 records of retinitis pigmentosa 96, 98, 99, 100 and 101 link to HGNC 10521, 25018, 5386, 21485 and 2074, which genenames.org resolves to SAG, TMEM216, IDH3G, TBC1D32 and CLN3, and the retinitis pigmentosa 97 record links to no RNU4 or RNU6 gene.

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Heterozygous variants are transmitted dominantly from either parent in most families (61%), and arise de novo in some isolated cases. The RNU6 n.55_56insG variant was shown to be de novo in eight sporadic cases, while n.56_57insG was seen only in dominant pedigrees. Nine obligate RNU4-2 carriers had no visual symptoms, so penetrance is incomplete for RNU4-2 variants.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (4 references)

PMID:41513982 SUPPORT Human clinical

"in our study most families with RP (61%) bore RNU4-2 and RNU6 changes as inherited variants"

Most families carry the variant by inheritance rather than de novo.

PMID:41513982 SUPPORT Human clinical

"Notably, n.55_56insG was confirmed to be a de novo event in eight individuals, clinically identified as sporadic cases."

Confirmed de novo occurrence in sporadic cases.

PMID:41513982 SUPPORT Human clinical

"Of note, incomplete penetrance was observed for nine obligate carriers, without visual symptoms"

Incomplete penetrance among RNU4-2 obligate carriers.

+ 1 more reference

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Discussions and Knowledge Gaps

2

Does delayed snRNP assembly cause mis-splicing in photoreceptors, and if so of which transcripts?

KNOWLEDGE GAP OPEN u4u6_rp_no_detected_missplicing

Attached to

pathophysiology#Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly pathophysiology#Photoreceptor Degeneration

Leukocyte RNA-seq from nine patients found no consistent splicing change, and the two shared events differed by under 10%. Leukocytes are not the affected tissue, and the snRNA demand of retina is several-fold higher, so a retina-restricted splicing defect is not excluded. Until splicing is measured in patient-derived photoreceptors or retinal organoids, the step between the assembly delay and photoreceptor degeneration is unknown, which is why this entry does not conform to the module's mis-splicing node.

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"we did not observe any major splicing anomalies in transcripts from patients with RP, with the only two significant events showing differences below 10% in expression"

The absence of a splicing signature in patient blood that leaves the gap open.

Why does RNU6-7 carry no pathogenic variant when the other four identical RNU6 paralogs do?

OPEN QUESTION OPEN u4u6_rp_rnu6_7_spared

Attached to

genetic#RNU6-1

RNU6-7 has the same chromatin marks of active transcription in retina as the other paralogs, so differential expression does not explain it, and the recurrent n.55_56insG variant is present in RNU6-7 in control individuals of African ancestry in gnomAD and All of Us. The authors leave this unresolved. It bears on whether every RNU6 paralog contributes equally to the retinal U6 pool.

Show evidence (2 references)

PMID:41513982 SUPPORT Human clinical

"We also identified the recurrent variant n.55_56insG in RNU6-7 in six control individuals of African or African American ancestry in gnomAD v.4.1"

The recurrent pathogenic insertion occurs in RNU6-7 in unaffected controls.

PMID:41513982 SUPPORT Human clinical

"These seemingly contradictory observations merit further investigations in future studies."

The authors state the question is open.

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Pathophysiology

3

U4/U6 Three-Way Junction snRNA Variant

A heterozygous variant in RNU4-2 or in one of the RNU6 paralogs changes the sequence of U4 or U6 snRNA within the three-way junction of the U4/U6 duplex, bounded by stem I, stem II and the U4 5' stem-loop. RNA folding predictions suggest the RNU4-2 variants enlarge the internal loop and the RNU6 insertions lengthen stem I and reorient the 5' stem-loop; the authors note these structural effects are not yet verified experimentally. Because only about a quarter of cellular U4 or a tenth of U6 would be mutant, and because common benign variants at the same position appear not to enter the assembly pathway, the authors favour a gain-of-function or dominant-negative effect over haploinsufficiency. Evidence for the variant spectrum is from human genetic studies; the structural mapping is computational.

RNU4-2 hgnc:10193 RNU6-1 hgnc:10227 RNU6-2 hgnc:34270 RNU6-8 hgnc:34285 RNU6-9 hgnc:34269

U4/U6 snRNP GO:0071001

Downstream

Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly

Show evidence (3 references)

PMID:41513982 SUPPORT Human clinical

"These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis."

Localizes all RP variants to the U4/U6 three-way junction.

PMID:41513982 SUPPORT Computational

"All RP variants are predicted to map in spatial proximity with each other, within the three-way junction delimited by stem-I and stem-II of the U4/U6 duplex and the 5′ stem-loop of U4"

Structural modelling places the variants together in the junction.

PMID:41513982 SUPPORT In vitro / ex vivo

"suggesting that pathogenesis could result from a gain-of-function or dominant-negative mechanism, rather than from haploinsufficiency"

The authors' reading of their binding assays on the molecular mechanism.

Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly

Ectopically expressed U4 and U6 snRNAs carrying RP variants co-purify more SART3 and, partially, more PRPF31, while binding of the U5 snRNP protein SNRNP200 is unchanged or reduced. The authors read this as a modest delay in the transition from the U4/U6 di-snRNP to the U4/U6.U5 tri-snRNP, not a failure of assembly: all changes were under 1.5-fold. The ReNU variant n.64_65insT tested alongside showed no significant change, and the RP and ReNU variants did not differ significantly from each other. Evidence is from cell-based immunoprecipitation assays.

delayed spliceosomal tri-snRNP complex assembly GO:0000244 ⚠ ABNORMAL

U4/U6 x U5 tri-snRNP complex GO:0046540

Downstream

Photoreceptor Degeneration

Show evidence (3 references)

PMID:41513982 SUPPORT In vitro / ex vivo

"The combined results showed an increased association of snRNA constructs with RP variants with SART3 and partially with PRPF31, while the interaction with SNRNP200 was unchanged or reduced"

The binding changes measured for the RP variant snRNAs.

PMID:41513982 SUPPORT In vitro / ex vivo

"Taken together, the results indicate that RP pathogenic variants have potentially a specific dominant effect on snRNP biogenesis and delay the assembly process at the di-snRNP stage."

The authors' conclusion that assembly is delayed at the di-snRNP stage.

PMID:41513982 SUPPORT In vitro / ex vivo

"we interpret these data as indicating that snRNA variants associated with RP are unlikely to prevent the assembly of spliceosomal complexes"

Bounds the claim to a delay rather than a block in assembly.

Photoreceptor Degeneration

Progressive loss of rod and then cone photoreceptor function produces classical retinitis pigmentosa. The photoreceptor degeneration itself is known from clinical examination and electrophysiology in patients; how the snRNP assembly delay leads to it is not shown. Conformance to the splicing-sensitive cell failure node rests on human donor-tissue RNA-seq showing higher U4 and U6 snRNA expression in neurosensory retina and retinal pigment epithelium than in choroid, which the authors take as a high retinal demand for snRNAs, and on the authors' proposal that the variants cause photoreceptor death while sparing brain development. No splicing defect has been measured in retinal cells.

rod photoreceptor CL:0000604 cone photoreceptor CL:0000573

Downstream

Rod-cone dystrophy

Nyctalopia

Constriction of peripheral visual field

Reduced visual acuity

Show evidence (3 references)

PMID:41513982 SUPPORT Human clinical

"The overall phenotype across all cases was consistent with classical RP, based on clinical examination and electrophysiological testing"

Patients have the photoreceptor degeneration of classical retinitis pigmentosa.

PMID:41513982 SUPPORT Human clinical

"NSR and RPE had higher expression of RNU4 (2.51×) and RNU6 (6.09×) with respect to the choroid"

Higher U4 and U6 expression in the retinal layers affected by the disease.

PMID:41513982 SUPPORT INDIRECT Human clinical

"It is therefore plausible that the RP variants identified in RNU4-2 and RNU6 paralogs could lead to photoreceptor death and subsequent visual loss, while having no influence on the development of the brain."

The authors propose photoreceptor death as the cellular outcome; it is not measured directly.

⬡

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.

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Phenotypes

7

Rod-cone dystrophy OBLIGATE Ophthalmological HP:0000510

Show evidence (2 references)

PMID:41513982 SUPPORT Human clinical

"The overall phenotype across all cases was consistent with classical RP, based on clinical examination and electrophysiological testing, with symptomatic onset predominantly in adolescence"

Classical retinitis pigmentosa in all cases, starting mostly in adolescence.

PMID:41513982 SUPPORT Human clinical

"particularly showing an earlier onset—contrasting with the generally milder prognosis observed in most other adRP types"

Onset is earlier than in most dominant retinitis pigmentosa.

Nyctalopia Ophthalmological HP:0000662

Show evidence (1 reference)

PMID:41513982 SUPPORT INDIRECT Human clinical

"symptomatic onset (night-blindness and peripheral vision loss) in nonsyndromic adRP begins later in life"

Names night blindness as the presenting symptom. The sentence is about nonsyndromic dominant retinitis pigmentosa in general, contrasted with ReNU syndrome, rather than a count in this cohort.

Constriction of peripheral visual field Ophthalmological HP:0001133

Show evidence (1 reference)

PMID:41513982 SUPPORT INDIRECT Human clinical

"symptomatic onset (night-blindness and peripheral vision loss) in nonsyndromic adRP begins later in life"

Names peripheral vision loss among the presenting symptoms; as for nyctalopia, the sentence describes dominant retinitis pigmentosa in general.

Reduced visual acuity Ophthalmological HP:0007663

Show evidence (1 reference)

PMID:41513982 SUPPORT INDIRECT Human clinical

"with severe central vision loss usually occurring after the onset of reproductive age"

Central vision is lost late in the course. The sentence describes nonsyndromic dominant retinitis pigmentosa in general.

Cystoid macular edema FREQUENT Ophthalmological HP:0011505

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"other concurrent ocular disease features were noted across individuals in the cohort: cystoid macular edema (55.9%)"

Frequency of cystoid macular edema across the cohort.

Cataract OCCASIONAL Ophthalmological HP:0000518

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"non-age-related lens opacities (23.6%) and various vitreomacular complications (30.6%)"

Frequency of non-age-related lens opacities across the cohort.

Vitreomacular complications FREQUENT Ophthalmological HP:0004327

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"non-age-related lens opacities (23.6%) and various vitreomacular complications (30.6%)"

Frequency of vitreomacular complications across the cohort. The sentence does not say which complications were observed.

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Genetic Associations

5

RNU4-2

Gene: RNU4-2 hgnc:10193 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:41513982 SUPPORT Human clinical

"Altogether, recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families"

Establishes RNU4-2 as a cause of dominant retinitis pigmentosa.

PMID:41974596 SUPPORT REVIEW SYNTHESIS Human clinical

"variants in noncoding small nuclear RNA genes, RNU4-2 and four RNU6 paralogs, represent a previously unrecognized cause of autosomal dominant retinitis pigmentosa"

An independent commentary restating the gene-disease finding.

Variants (2)

n.18_19insA Pathogenic

insertion

Single-nucleotide insertion between stem II and the U4 5' stem-loop (NR_003137.2:n.18_19insA). Found in the founding family and three further families, and once de novo; significantly enriched in cases over gnomAD and All of Us controls.

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"The n.18_19insA allele was significantly enriched in the RP cohort compared with both the gnomAD and the All of Us databases"

Case-control enrichment of the insertion.

n.56T>C Pathogenic

single nucleotide variant

Disrupts the first base pair of the U4/U6 duplex in stem I. Recurred in four families in the initial cohort and six more in later screening, and was absent from controls. It did not score significantly in saturation genome editing of RNU4-2 in HAP1 cells, which reads out cell fitness rather than retinal function.

Show evidence (2 references)

PMID:41513982 SUPPORT Human clinical

"one of which (n.56T>C) recurred in eight individuals from four families"

Recurrence of n.56T>C in the initial cohort.

PMID:41951737 SUPPORT In vitro / ex vivo

"It is notable, for instance, that a variant recently associated with retinitis pigmentosa (n.56T>C) did not score significantly."

The variant has no detectable fitness effect in the HAP1 saturation editing assay.

RNU6-1

Gene: RNU6-1 hgnc:10227 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"occurring in four of the five RNU6 paralogs: RNU6-1, RNU6-2, RNU6-8 and RNU6-9, while n.56_57insG was present in ten individuals from five families, in RNU6-1, RNU6-2 and RNU6-9"

Places both recurrent U6 variants in RNU6-1.

RNU6-2

Gene: RNU6-2 hgnc:34270 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"The n.55_56insG insertion recurred at the exact relative position in RNU6-2, RNU6-8 and RNU6-9"

Recurrence of the U6 insertion in RNU6-2.

RNU6-8

Gene: RNU6-8 hgnc:34285 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"The n.55_56insG insertion recurred at the exact relative position in RNU6-2, RNU6-8 and RNU6-9"

Recurrence of the U6 insertion in RNU6-8.

RNU6-9

Gene: RNU6-9 hgnc:34269 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"Another insertion, n.56_57insG, was identified in two unrelated families (once in RNU6-2 and once in RNU6-9, four cases in total"

The second U6 insertion in RNU6-9 and RNU6-2.

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Diagnosis

1

Genome sequencing or targeted snRNA gene sequencing

Exome capture designs omit snRNA genes, so these variants are found by genome sequencing or by targeted Sanger sequencing of RNU4-2 and the RNU6 paralogs in exome-negative retinitis pigmentosa.

Show evidence (1 reference)

PMID:41513982 SUPPORT Human clinical

"mainstream sequencing approaches are biased towards DNA-capturing procedures that do not include snRNA genes"

Explains why exome testing misses these variants.

{ }

Source YAML

click to show

name: U4 and U6 snRNA Gene-Related Retinitis Pigmentosa
creation_date: "2026-11-01T21:45:46Z"
category: Mendelian
description: >-
  U4 and U6 snRNA gene-related retinitis pigmentosa is a nonsyndromic,
  dominantly transmitted rod-cone dystrophy caused by heterozygous variants in
  RNU4-2, which encodes the U4 small nuclear RNA, or in four of the five
  identical RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode the
  U6 small nuclear RNA. Four recurrent variants account for the reported
  families: n.18_19insA and n.56T>C in RNU4-2, and n.55_56insG and n.56_57insG
  in the RNU6 paralogs. Variants are inherited in most families and arise de
  novo in some isolated cases, and RNU4-2 variants show incomplete penetrance.
  All of them lie in the three-way junction of the U4/U6 duplex, where the
  duplex binds the tri-snRNP splicing factors PRPF31 and PRPF3, both themselves
  causes of dominant retinitis pigmentosa. This is a different structural
  element from the RNU4-2 region mutated in ReNU syndrome, and patients have no
  neurodevelopmental phenotype. In ectopic expression assays the variant snRNAs
  bind the di-snRNP markers SART3 and PRPF31 more strongly, consistent with a
  delay in snRNP biogenesis at the di-snRNP stage rather than a failure of
  assembly, and no consistent splicing change was found in patient leukocytes.
  The presentation is classical retinitis pigmentosa with onset mostly in
  adolescence, with frequent cystoid macular edema, lens opacities and
  vitreomacular complications. In a
  cohort of 4,722 genetically undiagnosed retinitis pigmentosa cases the
  variants were estimated to explain about 1.4% of cases. Because snRNA genes
  are not captured by exome sequencing, affected individuals are usually
  exome-negative. MONDO has no class for this disease, so disease_term carries
  a free-text preferred term with no binding and the retinitis pigmentosa class
  is recorded as a broad match.
disease_term:
  preferred_term: U4 and U6 snRNA gene-related retinitis pigmentosa
parents:
- Retinitis pigmentosa
synonyms:
- RNU4-2 and RNU6-related retinitis pigmentosa
- RNU4- and RNU6-associated retinitis pigmentosa
- snRNA-related autosomal dominant retinitis pigmentosa
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019200
      label: retinitis pigmentosa
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      This entry is the subset of retinitis pigmentosa caused by dominant
      variants in RNU4-2 and the RNU6 paralogs, so the whole retinitis
      pigmentosa class is broader than it. A narrower MONDO class was searched
      for on 2026-11-01 with the OLS4 search API restricted to MONDO. The query
      "RNU4-2" returned one class, MONDO:0008871 microcephalic osteodysplastic
      primordial dwarfism type I, whose definition names RNU4ATAC, not RNU4-2.
      The queries "RNU6", "RNU6-1", "U4 snRNA", "U6 snRNA" and "snRNA retinitis
      pigmentosa" returned no classes. The newest numbered classes,
      retinitis pigmentosa 96 to 101 (exact-label OLS4 search; "retinitis
      pigmentosa 102" returned nothing), are not this disease: the OLS4 v2
      records of retinitis pigmentosa 96, 98, 99, 100 and 101 link to HGNC
      10521, 25018, 5386, 21485 and 2074, which genenames.org resolves to SAG,
      TMEM216, IDH3G, TBC1D32 and CLN3, and the retinitis pigmentosa 97 record
      links to no RNU4 or RNU6 gene.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Heterozygous variants are transmitted dominantly from either parent in
    most families (61%), and arise de novo in some isolated cases. The RNU6
    n.55_56insG variant was shown to be de novo in eight sporadic cases, while
    n.56_57insG was seen only in dominant pedigrees. Nine obligate RNU4-2
    carriers had no visual symptoms, so penetrance is incomplete for RNU4-2
    variants.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in our study most families with RP (61%) bore RNU4-2 and RNU6 changes as inherited variants"
    explanation: Most families carry the variant by inheritance rather than de novo.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, n.55_56insG was confirmed to be a de novo event in eight individuals, clinically identified as sporadic cases."
    explanation: Confirmed de novo occurrence in sporadic cases.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, incomplete penetrance was observed for nine obligate carriers, without visual symptoms"
    explanation: Incomplete penetrance among RNU4-2 obligate carriers.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not observe the same trend for RP, with variants being inherited from either of the parents"
    explanation: Transmission occurs from mothers and fathers, unlike the maternal bias reported for ReNU syndrome.
pathophysiology:
- name: U4/U6 Three-Way Junction snRNA Variant
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    A heterozygous variant in RNU4-2 or in one of the RNU6 paralogs changes the
    sequence of U4 or U6 snRNA within the three-way junction of the U4/U6
    duplex, bounded by stem I, stem II and the U4 5' stem-loop. RNA folding
    predictions suggest the RNU4-2 variants enlarge the internal loop and the
    RNU6 insertions lengthen stem I and reorient the 5' stem-loop; the authors
    note these structural effects are not yet verified experimentally. Because
    only about a quarter of cellular U4 or a tenth of U6 would be mutant, and
    because common benign variants at the same position appear not to enter the
    assembly pathway, the authors favour a gain-of-function or dominant-negative
    effect over haploinsufficiency. Evidence for the variant spectrum is from
    human genetic studies; the structural mapping is computational.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: RNU4-2
    term:
      id: hgnc:10193
      label: RNU4-2
  - preferred_term: RNU6-1
    term:
      id: hgnc:10227
      label: RNU6-1
  - preferred_term: RNU6-2
    term:
      id: hgnc:34270
      label: RNU6-2
  - preferred_term: RNU6-8
    term:
      id: hgnc:34285
      label: RNU6-8
  - preferred_term: RNU6-9
    term:
      id: hgnc:34269
      label: RNU6-9
  cellular_components:
  - preferred_term: U4/U6 snRNP
    term:
      id: GO:0071001
      label: U4/U6 snRNP
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis."
    explanation: Localizes all RP variants to the U4/U6 three-way junction.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "All RP variants are predicted to map in spatial proximity with each other, within the three-way junction delimited by stem-I and stem-II of the U4/U6 duplex and the 5′ stem-loop of U4"
    explanation: Structural modelling places the variants together in the junction.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "suggesting that pathogenesis could result from a gain-of-function or dominant-negative mechanism, rather than from haploinsufficiency"
    explanation: The authors' reading of their binding assays on the molecular mechanism.
  downstream:
  - target: Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41513982
      reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The mutated and neighboring U4 and U6 nucleotides detected in RP cases directly participate in the binding of PRPF31 and PRPF3"
      explanation: >-
        Analysis of an existing cryo-EM structure (PDB 6QW6) shows the mutated
        nucleotides contact the tri-snRNP factors whose binding is altered.
- name: Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly
  description: >-
    Ectopically expressed U4 and U6 snRNAs carrying RP variants co-purify more
    SART3 and, partially, more PRPF31, while binding of the U5 snRNP protein
    SNRNP200 is unchanged or reduced. The authors read this as a modest delay in
    the transition from the U4/U6 di-snRNP to the U4/U6.U5 tri-snRNP, not a
    failure of assembly: all changes were under 1.5-fold. The ReNU variant
    n.64_65insT tested alongside showed no significant change, and the RP and
    ReNU variants did not differ significantly from each other. Evidence is from
    cell-based immunoprecipitation assays.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: U4/U6 x U5 tri-snRNP complex
    term:
      id: GO:0046540
      label: U4/U6 x U5 tri-snRNP complex
  biological_processes:
  - preferred_term: delayed spliceosomal tri-snRNP complex assembly
    term:
      id: GO:0000244
      label: spliceosomal tri-snRNP complex assembly
    modifier: ABNORMAL
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The combined results showed an increased association of snRNA constructs with RP variants with SART3 and partially with PRPF31, while the interaction with SNRNP200 was unchanged or reduced"
    explanation: The binding changes measured for the RP variant snRNAs.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Taken together, the results indicate that RP pathogenic variants have potentially a specific dominant effect on snRNP biogenesis and delay the assembly process at the di-snRNP stage."
    explanation: The authors' conclusion that assembly is delayed at the di-snRNP stage.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we interpret these data as indicating that snRNA variants associated with RP are unlikely to prevent the assembly of spliceosomal complexes"
    explanation: Bounds the claim to a delay rather than a block in assembly.
  downstream:
  - target: Photoreceptor Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Photoreceptor Degeneration
  conforms_to: "spliceosome_component_dysfunction#Failure of Splicing-Sensitive Cell Populations"
  description: >-
    Progressive loss of rod and then cone photoreceptor function produces
    classical retinitis pigmentosa. The photoreceptor degeneration itself is
    known from clinical examination and electrophysiology in patients; how the
    snRNP assembly delay leads to it is not shown. Conformance to the
    splicing-sensitive cell failure node rests on human donor-tissue RNA-seq
    showing higher U4 and U6 snRNA expression in neurosensory retina and
    retinal pigment epithelium than in choroid, which the authors take as a
    high retinal demand for snRNAs, and on the authors' proposal that the
    variants cause photoreceptor death while sparing brain development. No
    splicing defect has been measured in retinal cells.
  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
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall phenotype across all cases was consistent with classical RP, based on clinical examination and electrophysiological testing"
    explanation: Patients have the photoreceptor degeneration of classical retinitis pigmentosa.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NSR and RPE had higher expression of RNU4 (2.51×) and RNU6 (6.09×) with respect to the choroid"
    explanation: Higher U4 and U6 expression in the retinal layers affected by the disease.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is therefore plausible that the RP variants identified in RNU4-2 and RNU6 paralogs could lead to photoreceptor death and subsequent visual loss, while having no influence on the development of the brain."
    explanation: The authors propose photoreceptor death as the cellular outcome; it is not measured directly.
  downstream:
  - target: Rod-cone dystrophy
  - target: Nyctalopia
  - target: Constriction of peripheral visual field
  - target: Reduced visual acuity
phenotypes:
- name: Rod-cone dystrophy
  category: Ophthalmological
  frequency: OBLIGATE
  description: >-
    Classical retinitis pigmentosa, with symptomatic onset mostly in
    adolescence; the authors note onset is earlier than in most other forms of
    dominant retinitis pigmentosa.
  phenotype_term:
    preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall phenotype across all cases was consistent with classical RP, based on clinical examination and electrophysiological testing, with symptomatic onset predominantly in adolescence"
    explanation: Classical retinitis pigmentosa in all cases, starting mostly in adolescence.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "particularly showing an earlier onset—contrasting with the generally milder prognosis observed in most other adRP types"
    explanation: Onset is earlier than in most dominant retinitis pigmentosa.
- name: Nyctalopia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic onset (night-blindness and peripheral vision loss) in nonsyndromic adRP begins later in life"
    explanation: >-
      Names night blindness as the presenting symptom. The sentence is about
      nonsyndromic dominant retinitis pigmentosa in general, contrasted with
      ReNU syndrome, rather than a count in this cohort.
- name: Constriction of peripheral visual field
  category: Ophthalmological
  phenotype_term:
    preferred_term: Peripheral vision loss
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic onset (night-blindness and peripheral vision loss) in nonsyndromic adRP begins later in life"
    explanation: >-
      Names peripheral vision loss among the presenting symptoms; as for
      nyctalopia, the sentence describes dominant retinitis pigmentosa in
      general.
- name: Reduced visual acuity
  category: Ophthalmological
  description: Severe central vision loss, usually after the onset of reproductive age.
  phenotype_term:
    preferred_term: Central vision loss
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "with severe central vision loss usually occurring after the onset of reproductive age"
    explanation: >-
      Central vision is lost late in the course. The sentence describes
      nonsyndromic dominant retinitis pigmentosa in general.
- name: Cystoid macular edema
  category: Ophthalmological
  frequency: FREQUENT
  description: Reported in 55.9% of individuals in the cohort.
  phenotype_term:
    preferred_term: Cystoid macular edema
    term:
      id: HP:0011505
      label: Cystoid macular edema
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other concurrent ocular disease features were noted across individuals in the cohort: cystoid macular edema (55.9%)"
    explanation: Frequency of cystoid macular edema across the cohort.
- name: Cataract
  category: Ophthalmological
  frequency: OCCASIONAL
  description: Non-age-related lens opacities in 23.6% of individuals in the cohort.
  phenotype_term:
    preferred_term: Non-age-related lens opacities
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-age-related lens opacities (23.6%) and various vitreomacular complications (30.6%)"
    explanation: Frequency of non-age-related lens opacities across the cohort.
- name: Vitreomacular complications
  category: Ophthalmological
  frequency: FREQUENT
  description: >-
    Vitreomacular complications in 30.6% of individuals in the cohort. The
    source groups them as "various vitreomacular complications" without naming
    the individual findings, so the binding stays at the general vitreous
    abnormality term.
  phenotype_term:
    preferred_term: Vitreomacular complications
    term:
      id: HP:0004327
      label: Abnormal vitreous humor morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-age-related lens opacities (23.6%) and various vitreomacular complications (30.6%)"
    explanation: >-
      Frequency of vitreomacular complications across the cohort. The sentence
      does not say which complications were observed.
genetic:
- name: RNU4-2
  gene_term:
    preferred_term: RNU4-2
    term:
      id: hgnc:10193
      label: RNU4-2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    RNU4-2 encodes U4 snRNA, which pairs with U6 in the U4/U6 di-snRNP and
    U4/U6.U5 tri-snRNP. Recurrent RP variants were found in 41 affected
    individuals from 15 families. The paralog RNU4-1, which differs at four
    positions, carried no case-enriched variant. RNU4-2 is the same gene that
    causes ReNU syndrome, through variants in a different structural region; it
    is a non-coding gene, so the snRNA has no protein molecular function.
  variants:
  - name: n.18_19insA
    variant_type: insertion
    clinical_significance: PATHOGENIC
    description: >-
      Single-nucleotide insertion between stem II and the U4 5' stem-loop
      (NR_003137.2:n.18_19insA). Found in the founding family and three further
      families, and once de novo; significantly enriched in cases over gnomAD
      and All of Us controls.
    evidence:
    - reference: PMID:41513982
      reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The n.18_19insA allele was significantly enriched in the RP cohort compared with both the gnomAD and the All of Us databases"
      explanation: Case-control enrichment of the insertion.
  - name: n.56T>C
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    description: >-
      Disrupts the first base pair of the U4/U6 duplex in stem I. Recurred in
      four families in the initial cohort and six more in later screening, and
      was absent from controls. It did not score significantly in saturation
      genome editing of RNU4-2 in HAP1 cells, which reads out cell fitness
      rather than retinal function.
    evidence:
    - reference: PMID:41513982
      reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "one of which (n.56T>C) recurred in eight individuals from four families"
      explanation: Recurrence of n.56T>C in the initial cohort.
    - reference: PMID:41951737
      reference_title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "It is notable, for instance, that a variant recently associated with retinitis pigmentosa (n.56T>C) did not score significantly."
      explanation: The variant has no detectable fitness effect in the HAP1 saturation editing assay.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, recurrent variants in RNU4-2 were identified in 41 affected individuals from 15 families"
    explanation: Establishes RNU4-2 as a cause of dominant retinitis pigmentosa.
  - reference: PMID:41974596
    reference_title: "A new era for the dark genome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "variants in noncoding small nuclear RNA genes, RNU4-2 and four RNU6 paralogs, represent a previously unrecognized cause of autosomal dominant retinitis pigmentosa"
    explanation: An independent commentary restating the gene-disease finding.
- name: RNU6-1
  gene_term:
    preferred_term: RNU6-1
    term:
      id: hgnc:10227
      label: RNU6-1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    One of five identical RNU6 paralogs encoding U6 snRNA. Carries both
    recurrent RNU6 variants, n.55_56insG and n.56_57insG, which are predicted
    to lengthen stem I by three base pairs and reorient the U4 5' stem-loop.
    The RNU6 paralogs together account for 112 affected individuals from 52
    families. Non-coding gene; the snRNA has no protein molecular function.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "occurring in four of the five RNU6 paralogs: RNU6-1, RNU6-2, RNU6-8 and RNU6-9, while n.56_57insG was present in ten individuals from five families, in RNU6-1, RNU6-2 and RNU6-9"
    explanation: Places both recurrent U6 variants in RNU6-1.
- name: RNU6-2
  gene_term:
    preferred_term: RNU6-2
    term:
      id: hgnc:34270
      label: RNU6-2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    U6 snRNA paralog. Carries n.55_56insG and n.56_57insG. Non-coding gene;
    the snRNA has no protein molecular function.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The n.55_56insG insertion recurred at the exact relative position in RNU6-2, RNU6-8 and RNU6-9"
    explanation: Recurrence of the U6 insertion in RNU6-2.
- name: RNU6-8
  gene_term:
    preferred_term: RNU6-8
    term:
      id: hgnc:34285
      label: RNU6-8
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    U6 snRNA paralog. Carries n.55_56insG only. Non-coding gene; the snRNA has
    no protein molecular function.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The n.55_56insG insertion recurred at the exact relative position in RNU6-2, RNU6-8 and RNU6-9"
    explanation: Recurrence of the U6 insertion in RNU6-8.
- name: RNU6-9
  gene_term:
    preferred_term: RNU6-9
    term:
      id: hgnc:34269
      label: RNU6-9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    U6 snRNA paralog. Carries n.55_56insG and n.56_57insG. Non-coding gene;
    the snRNA has no protein molecular function.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Another insertion, n.56_57insG, was identified in two unrelated families (once in RNU6-2 and once in RNU6-9, four cases in total"
    explanation: The second U6 insertion in RNU6-9 and RNU6-2.
diagnosis:
- name: Genome sequencing or targeted snRNA gene sequencing
  description: >-
    Exome capture designs omit snRNA genes, so these variants are found by
    genome sequencing or by targeted Sanger sequencing of RNU4-2 and the RNU6
    paralogs in exome-negative retinitis pigmentosa.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mainstream sequencing approaches are biased towards DNA-capturing procedures that do not include snRNA genes"
    explanation: Explains why exome testing misses these variants.
discussions:
- discussion_id: u4u6_rp_no_detected_missplicing
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Increased Di-snRNP Factor Binding and Delayed Tri-snRNP Assembly
  - pathophysiology#Photoreceptor Degeneration
  prompt: >-
    Does delayed snRNP assembly cause mis-splicing in photoreceptors, and if
    so of which transcripts?
  rationale: >-
    Leukocyte RNA-seq from nine patients found no consistent splicing change,
    and the two shared events differed by under 10%. Leukocytes are not the
    affected tissue, and the snRNA demand of retina is several-fold higher, so
    a retina-restricted splicing defect is not excluded. Until splicing is
    measured in patient-derived photoreceptors or retinal organoids, the step
    between the assembly delay and photoreceptor degeneration is unknown, which
    is why this entry does not conform to the module's mis-splicing node.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we did not observe any major splicing anomalies in transcripts from patients with RP, with the only two significant events showing differences below 10% in expression"
    explanation: The absence of a splicing signature in patient blood that leaves the gap open.
- discussion_id: u4u6_rp_rnu6_7_spared
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - genetic#RNU6-1
  prompt: >-
    Why does RNU6-7 carry no pathogenic variant when the other four identical
    RNU6 paralogs do?
  rationale: >-
    RNU6-7 has the same chromatin marks of active transcription in retina as
    the other paralogs, so differential expression does not explain it, and the
    recurrent n.55_56insG variant is present in RNU6-7 in control individuals
    of African ancestry in gnomAD and All of Us. The authors leave this
    unresolved. It bears on whether every RNU6 paralog contributes equally to
    the retinal U6 pool.
  evidence:
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified the recurrent variant n.55_56insG in RNU6-7 in six control individuals of African or African American ancestry in gnomAD v.4.1"
    explanation: The recurrent pathogenic insertion occurs in RNU6-7 in unaffected controls.
  - reference: PMID:41513982
    reference_title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These seemingly contradictory observations merit further investigations in future studies."
    explanation: The authors state the question is open.
references:
- reference: PMID:41513982
  title: "De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa."
- reference: PMID:41951737
  title: "Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders."
- reference: PMID:41974596
  title: "A new era for the dark genome."

📚

References & Deep Research

References

3

PMID:41513982

De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa.

No top-level findings curated for this source.

PMID:41951737

Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders.

No top-level findings curated for this source.

PMID:41974596

A new era for the dark genome.

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.

Evaluations and curation notes (1)

Review round: vitreomacular complications phenotype; claude_code deep research · 2026-11-01T23:08:38Z · View source

Answered the automated review on PR 16292. Added a Vitreomacular complications phenotype (frequency FREQUENT, 30.6% of the cohort, inside the HPO 30-79% band) bound to HP:0004327 Abnormal vitreous humor morphology with coarse_binding_basis SOURCE_UNSPECIFIED, because PMID:41513982 says only 'various vitreomacular complications' and names no individual finding. HP:0004327 is not in the coarse set, so check-coarse-phenotypes does not require the basis; it is declared anyway so the reason for the general binding is recorded, and the companion check (none for this value) passes. The evidence item reuses the PMID:41513982 sentence already cited for cataract, graded HUMAN_CLINICAL as there. The description now lists vitreomacular complications with cystoid macular edema and lens opacities. Ran just research-disorder claude_code for this entry (research/U4_and_U6_snRNA_Gene-Related_Retinitis_Pigmentosa-deep-research-claude_code.md and its citations sidecar). Its 4 references all resolved and no term was unresolved. It rests on the same Quinodoz/Rivolta cohort as PMID:41513982, read through the earlier medRxiv preprint (PMID:39830270), and reports no independent replication cohort, so it added no new primary cohort or finding to the entry. Its suggestion of epiretinal membrane for the vitreomacular complications was not taken because the source does not name that finding. The ~1.4% of undiagnosed retinitis pigmentosa figure stays in description prose: it is a diagnostic yield in an undiagnosed cohort, and no PrevalenceMeasureEnum value describes that measure.

Claude Code ▸

U4 and U6 snRNA Gene-Related Retinitis Pigmentosa: Research Report

claude-haiku-5-5, claude-opus-5-5 20 citations 2026-11-01T23:05:31.185045

U4 and U6 snRNA Gene-Related Retinitis Pigmentosa: Research Report

Causal genes: RNU4-2 (encodes U4 snRNA) and four RNU6 paralogs, RNU6-1, RNU6-2, RNU6-8 and RNU6-9 (each encodes U6 snRNA). Category: Mendelian, autosomal dominant, non-coding RNA genes.

What this report rests on. - Nearly everything here comes from one research group's work (Quinodoz, Rivolta and colleagues), in two versions: - a 2025 preprint, PMID:39830270 (PMC11741465); - the peer-reviewed paper, Nature Genetics 2026;58(1):169–179, PMID:41513982, DOI 10.1038/s41588-025-02451-4. - I read the preprint full text through PMC's BioC service. For the published paper I saw only the abstract. Variant counts come from the preprint unless marked otherwise, and the published counts are higher. - Abstract wording below is paraphrased or quoted in short fragments. Before any snippet goes into a KB evidence item, fetch it with just fetch-reference and check it. - I found no independent replication cohort. Genomics England PanelApp is the only external expert review.

1. Disease Information

Overview. - This is non-syndromic retinitis pigmentosa (RP) caused by heterozygous variants in RNU4-2 or in four of the five active RNU6 paralogs. - These genes make the U4 and U6 small nuclear RNAs (snRNAs). The two pair up into the U4/U6 duplex inside the U4/U6.U5 tri-snRNP, a core part of the major spliceosome. - The preprint abstract says the variants "invariably cluster in close proximity within the three-way junction" of the U4/U6 duplex (PMID:39830270). - That region binds the tri-snRNP proteins PRPF3, PRPF8 and PRPF31. All three are already known causes of autosomal dominant RP (adRP). So this disease extends the existing "splicing-factor RP" class from proteins to the snRNAs themselves.

Identifiers.

Resource	Status
MONDO	No ID supplied, and I found none. Check `just next-stubs` or OLS before binding one.
OMIM	None found. The disease was described in 2025–2026, so it may not be catalogued yet.
Orphanet	No specific entry found. The parent is RP, ORPHA:791.
ICD-10 / ICD-11	Parent codes only: H35.52 (hereditary retinal dystrophy); ICD-11 9B70 (retinitis pigmentosa).
MeSH	Retinitis Pigmentosa, D012174 (parent term).
Gene panels	Genomics England PanelApp, Retinal disorders panel 307: RNU6-1, RNU6-2, RNU6-8 and RNU6-9 are listed. RNU6-1 and RNU6-8 are rated green (diagnostic grade). PanelApp Australia lists RNU6-1 on its RP panel.

Synonyms: RNU4-2 and RNU6-related retinitis pigmentosa; RNU4- and RNU6-associated RP; snRNA-related adRP.

Source of the data: cohort and family studies — rare-disease genome sequencing, Genomics England 100,000 Genomes, and international inherited-retinal-disease cohorts. There are no EHR-derived data.

2. Etiology

What causes it - The cause is a heterozygous germline variant in RNU4-2 or in RNU6-1, -2, -8 or -9. The variant is either inherited or arises de novo. - The variants are small insertions or single-nucleotide changes, all at the U4/U6 three-way junction (see Section 4).

Genetic risk factors - The causal variants are the only known genetic risk factor. I found no data on modifier loci. - Penetrance is incomplete (Section 9), so modifiers may exist, but none have been identified.

Environmental risk factors: none described. This is a monogenic disease.

Protective factors - None established. - One finding may matter here. RNU6-7, the fifth active U6 paralog, carries no recurrent pathogenic variants. The same n.55_56insG insertion turns up in RNU6-7 in population controls of African ancestry (gnomAD allele frequency 0.014%; All of Us 0.013%). - The authors propose that RNU6-7 is only minimally incorporated into the spliceosome. This explains why the same variant in that paralog is tolerated; it is not a protective factor in the usual sense (PMID:39830270).

Gene–environment interactions: none reported.

3. Phenotypes

Source: the preprint's clinical summary (PMID:39830270).

Phenotype	Suggested HPO term (verify every CURIE)	Frequency / features
Rod–cone dystrophy / RP	HP:0000510 Rod-cone dystrophy	100% of affected individuals (defining feature)
Nyctalopia (night blindness)	HP:0000662 Nyctalopia	Usually the first symptom; adolescence to early adulthood
Constriction of peripheral visual field	HP:0001133 Constriction of peripheral visual field	Early symptom, progressive
Cystoid macular edema	HP:0011505 Cystoid macular edema	55.9%
Vitreomacular complications (e.g., epiretinal membrane, vitreomacular traction)	e.g., HP:0100014 Epiretinal membrane; check for a more fitting term	30.6% (preprint lumps these together)
Cataract, not age-related	HP:0000518 Cataract	23.6%. The authors say cataract appears to be more frequent than in many other RP types.
Reduced/abnormal ERG	HP:0000512 Abnormal electroretinogram	ERG shows "classical" RP features
Fundus findings: bone-spicule pigmentation, attenuated arterioles, waxy disc pallor	HP:0007737 Bone spicule pigmentation of the retina; HP:0007843 Attenuation of retinal blood vessels	Described only as "classical RP features"; no per-sign frequencies
Late central vision loss	HP:0000529 Progressive visual loss (and/or HP:0000572 Visual loss)	Occurs "well beyond reproductive age"

Characteristics - Onset: adolescence to early adulthood. This is earlier than most other adRP forms. - Severity: variable. Penetrance is incomplete. - Course: progressive.

Not part of this disease - Neurodevelopmental features. These are absent. RP-causing variants give non-syndromic retinal disease, whereas different RNU4-2 variants cause ReNU syndrome (see Section 4). - Lab abnormalities. None.

Quality of life: no disease-specific quality-of-life data. Extrapolating from RP in general, expect loss of night and peripheral vision, mobility limits and later reading impairment. Cataract and cystoid macular edema add treatable reductions in vision.

4. Genetic / Molecular Information

Causal genes. HGNC IDs must be looked up with runoak/HGNC; I am not quoting them from memory. Use lowercase hgnc: in the KB. - RNU4-2: a U4 snRNA gene on chromosome 12q24.31. It is the same gene that causes ReNU syndrome. - RNU6-1, RNU6-2, RNU6-8, RNU6-9: U6 snRNA paralogs. - RNU6-7: no pathogenic variants. - RNU4-1 (the other U4 paralog, which lies next to RNU4-2): no pathogenic variants at the two RP hotspots, and 63 likely-benign variants.

Pathogenic variants

All variants are germline and heterozygous. Counts are from the preprint.

Gene	Variant	Families / affected individuals (preprint)	Position in the structure
RNU4-2	n.18_19insA	Index family (8 affected, plus unaffected carriers); 3 more families (15 affected); plus 1 patient from another cohort	Between stem-II and the U4 5′ stem-loop; disrupts base-pairing and changes stem orientation
RNU4-2	n.56T>C	4 families / 7 individuals, then 4 more families / 5 affected	Disrupts base-pairing in stem-I. The same change at the equivalent site of RNU4-1 (NR_003925.1:n.56T>C) appears in 2 All of Us individuals of unknown phenotype.
RNU4-2 total		13 families, 36 affected (+27 untested affected relatives)
RNU6-1, -2, -8, -9	n.55_56insG	43 families, 89 individuals. De novo confirmed in 7 sporadic cases; suspected de novo in 12 more pedigrees.	Adds a G–U wobble pair and extends stem-I
RNU6-1, -2, -9	n.56_57insG	6 families, 10 individuals. One gnomAD v4.1 carrier in RNU6-2.	Same mechanism as n.55_56insG
RNU6 total		49 families, 99 affected (+112 untested relatives likely carrying the variant)

Updated counts - Preprint total: 135 individuals, 62 families. - Published paper and PanelApp: 153 individuals, 67 families. PanelApp reports n.55_56insG in 102 individuals from 47 unrelated families.

Classification and population data - Uncertain or benign variants (preprint): - RNU4-2: 10 VUS and 17 benign variants. - RNU6 paralogs: 20 VUS and 70 benign variants. - Benign controls that sit right next to the hotspots: - U6 n.55_56insT, with a cumulative gnomAD frequency of 0.12%; - U6 n.57T>G, seen in 21 unaffected people. - These show that the exact base inserted matters, not just its position. - ClinVar / ClinGen: I did not check ClinVar entries. There is no ClinGen gene-disease validity curation that I could find, so leave gene_disease_validity empty. - Constraint (gnomAD v4.1): cumulative allele frequency is 1.2% for RNU4-2 against 20.4% for RNU4-1. RNU4-2 is therefore far less tolerant of variation.

Functional consequence - The variants are thought to act by a dominant-negative or gain-of-function mechanism, not haploinsufficiency (see Section 6). - For functional_impact_category, DOMINANT_NEGATIVE is the authors' leading interpretation. It is inferred from co-IP data, not proven.

Modifiers, epigenetics, chromosomal changes - None reported. - Chromatin data (ATAC-seq and H3K27ac) show active marks at RNU4-1/-2 and at RNU6-1, -2, -7, -8 and -9. Of the 105 U4 and 1,312 U6 pseudogenes, only RNU4-8P had active marks, which the authors attribute to its proximity to the ACTR1B promoter. - This explains why only these few loci cause disease.

How this differs from ReNU syndrome (RNU4-2 neurodevelopmental disorder) - Variant location: ReNU variants (e.g., n.64_65insT) sit in stem III, a separate region of the duplex; RP variants sit at the three-way junction. - Transmission: ReNU variants are mostly de novo, and when inherited they come mostly through the mother. RP variants are mostly inherited, from either parent. - Frequency: ReNU accounts for about 0.4% of neurodevelopmental disorder cases. - In the co-IP assay, the ReNU variant did not produce the increased SART3/PRPF31 binding seen with RP variants (PMID:39830270). - Curation point: keep this RP entry separate from ReNU. They are allelic but distinct diseases.

5. Environmental Information

Not applicable. There are no environmental, lifestyle or infectious causes.

6. Mechanism / Pathophysiology

Causal chain

A heterozygous variant arises — an insertion or substitution at the U4/U6 three-way junction (U4 n.18_19insA or n.56T>C; U6 n.55_56insG or n.56_57insG). It is present in every cell, but only some cells take part in the disease.
This changes the duplex shape. It alters base-pairing in stem-I or stem-II, or the stem orientation of the U4/U6 duplex at the junction of stem-I, stem-II and the U4 5′ stem-loop. Evidence: structural modelling (computational).
This disturbs the binding surface for PRPF31, PRPF3 and PRPF8. In tri-snRNP structures, PRPF31 makes hydrogen bonds with 8 duplex residues in this region and PRPF3 with 3. Evidence: computational, from published cryo-EM structures.
Mutant snRNPs stall at the U4/U6 di-snRNP stage.
MS2-tagged mutant U4 or U6 expressed in cultured cells pulls down more SART3 and PRPF31 (di-snRNP markers), and somewhat more SNRNP200 (a U5 marker).
Benign controls and the ReNU variant do not do this.
Evidence: in vitro (the preprint text does not name the cell line).
Inferred: slower recycling or assembly of the tri-snRNP. Because the mutant RNAs sit alongside normal ones, the effect is dominant-negative or gain-of-function.
Inferred: spliceosome capacity becomes limiting in high-demand cells. No splicing defect has been shown, either globally or for specific transcripts. The authors suggest RP variants are milder than ReNU variants, delaying assembly without measurable pre-mRNA processing defects.
Inferred: rod photoreceptors degenerate, then cones. This is the same tissue selectivity seen in PRPF31-, PRPF8- and PRPF3-related RP, and is thought to reflect the very high transcriptional and splicing demand of photoreceptors and the RPE.
Retina and RPE express much more of these RNAs than choroid: RNU4 about 2.45-fold and RNU6 about 6.24-fold higher.
Clinical result: night blindness, then loss of peripheral field, then late loss of central vision. Cystoid macular edema and cataract are frequent extras.

Where the chain branches - The disease is either RNU4-2-driven (2 variants) or RNU6-driven (2 variants across 4 paralogs). Both converge on the same assembly intermediate. - Whether the primary cell injured is the photoreceptor or the RPE is not settled. In PRPF31 RP the RPE is thought to be affected early.

Suggested GO terms (verify each) - Spliceosomal tri-snRNP complex assembly: GO:0000244 - mRNA splicing, via spliceosome: GO:0000398 - U4/U6 snRNP (cellular component): GO:0071001 - U4/U6 x U5 tri-snRNP complex: GO:0046540 - Photoreceptor cell maintenance: GO:0045494 (expected DECREASED) - Retina homeostasis: GO:0001895

Suggested CL terms - Retinal rod cell: CL:0000604 - Retinal cone cell: CL:0000573 - Retinal pigment epithelial cell: CL:0002586

Molecular profiling: no transcriptomic, proteomic, single-cell or CRISPR-screen data are specific to this disease.

7. Anatomical Structures

Level	Structure	Suggested ontology term
Organ	Eye / retina	UBERON:0000966 retina
Organ	Lens (cataract)	UBERON:0000965 lens of camera-type eye
Organ	Macula (cystoid macular edema)	UBERON:0000053 macula lutea
Tissue	Photoreceptor layer; RPE	UBERON:0001782 pigmented layer of retina
Subcellular	Nucleus / nuclear speckles, Cajal body (snRNP assembly site)	GO:0005634 nucleus; GO:0015030 Cajal body

Laterality: bilateral and largely symmetric (typical of RP; not quantified for this disease).

8. Temporal Development

Onset: insidious, in adolescence to early adulthood. It is earlier than most adRP forms.
Progression:
The course runs from night blindness, to constricted visual fields, to loss of central vision.
The pace is slow; central vision is lost late, "well beyond reproductive age".
The disease lasts for life.
Remission: none.
Critical windows for intervention:
before photoreceptors are lost, for any future therapy;
monitoring for cystoid macular edema, which is common and treatable.

9. Inheritance and Population

Inheritance: autosomal dominant (HP:0000006). There are frequent de novo cases.
In the preprint, 67% of cases were inherited, from either parent.
De novo origin was confirmed in 7 cases and suspected in 12 more pedigrees.
The somatic-mosaicism term does not apply to this disease.
Penetrance: incomplete.
9 obligate carriers had no visual symptoms (4 of them deceased).
Non-penetrance was seen in 5 of 13 informative families (38%).
Of the living asymptomatic carriers who were examined, one was subclinically affected and one had no signs; three were not evaluated.
Expressivity: variable.
Anticipation: none. These are not repeat-expansion variants.
Founder effects: not described. The U6 n.55_56insG variant recurs in many unrelated families of diverse ancestry, which points to a mutational hotspot, not a founder.
Frequency among RP patients:
Preprint estimate: up to about 1.2% of undiagnosed RP and about 2.7% of undiagnosed adRP families. The basis was roughly 5,000 RP cases, about 40% undiagnosed, with about 30% of RP being adRP.
Published estimate: up to about 1.4% of otherwise undiagnosed RP.
Population prevalence: not estimated.
Parent RP prevalence is about 1 in 4,000. Multiplying this by the diagnostic-yield fraction would be an inference, not a sourced number. Do not enter a rate_per_100000.
Sex ratio: not reported. Expect it to be equal for an autosomal disease.

10. Diagnostics

Genetic testing - Exome sequencing and most standard RP panels miss these variants. snRNA genes are not exons, and the RNU6 paralogs are short, multi-copy and hard to map uniquely. - Recommended: - genome sequencing with snRNA loci deliberately analysed; - or targeted sequencing of RNU4-2 and RNU6-1/2/8/9, now on PanelApp's retinal disorders panel 307; - reanalysis of genome data from unsolved adRP and sporadic RP cases. - Read-mapping: U6 has more than 1,300 pseudogenes, so mapping must be paralog-aware, and confirmation (e.g., by Sanger sequencing with paralog-specific primers) is prudent. - Not useful here: chromosomal microarray, karyotype, FISH and mtDNA testing.

Clinical tests - full-field ERG (rod-cone pattern); - fundus photography and autofluorescence; - OCT (cystoid macular edema, ellipsoid zone loss); - visual fields (Goldmann or static); - slit-lamp exam for cataract. - Possible NCIT diagnosis terms: electroretinography, optical coherence tomography (look up CURIEs; do not use from memory).

Biomarkers: none.

Differential diagnosis - other adRP genes — especially PRPF31 (which shares incomplete penetrance), PRPF8, PRPF3, SNRNP200 and RHO; - ReNU syndrome (has neurodevelopmental features); - syndromic RP (e.g., Usher, Bardet–Biedl); - phenocopies (drug toxicity, autoimmune retinopathy).

Screening: cascade testing of relatives. Unaffected carriers need counselling because of incomplete penetrance.

11. Outcome / Prognosis

Life expectancy: normal. No mortality is attributable to the disease.
Morbidity: progressive visual disability, with central vision loss late in life. Cystoid macular edema (around 56%) and cataract (around 24%) cause additional, treatable vision loss.
Prognostic factors: none established. Comparisons by variant or gene (RNU4-2 vs RNU6) have not been reported.

12. Treatment

There is no disease-specific therapy. Management is the same as for RP in general.

Intervention	Suggested NCIT approach (verify CURIEs)
Treating cystoid macular edema with carbonic anhydrase inhibitors (oral acetazolamide, topical dorzolamide)	NCIT:C15986 Pharmacotherapy + `therapeutic_agent` (CHEBI acetazolamide / dorzolamide)
Cataract surgery	NCIT:C15329 Surgical Procedure (or a more specific cataract-extraction term after lookup)
Low-vision rehabilitation	NCIT:C15315 Rehabilitation
Genetic counselling	NCIT:C15240 Genetic Counseling

Experimental therapy and trials - No trials target this disease. - Gene augmentation is conceptually unsuitable for a dominant-negative non-coding RNA. Allele-specific knockdown or editing of the mutant snRNA copy is a theoretical approach, but none has been reported. - Mutation-independent approaches tested in RP generally (e.g., optogenetics, neuroprotection) could in principle apply.

Pharmacogenomics: not applicable.

13. Prevention

Primary: genetic counselling. Each child of a carrier has a 50% chance of inheriting the variant, with incomplete penetrance. Prenatal testing or preimplantation genetic testing is possible once the familial variant is known.
Secondary: cascade testing of relatives. Carriers should be monitored by ophthalmology.
Tertiary: regular OCT to catch cystoid macular edema, and timely cataract surgery.

14. Other Species

Natural animal disease: none known. I found no entries in OMIA (Online Mendelian Inheritance in Animals).
Conservation: U4 and U6 snRNAs, and the three-way-junction proteins PRPF31, PRPF3 and PRPF8, are highly conserved across eukaryotes from yeast to human. The U6 sequence is among the most conserved snRNAs.

15. Model Organisms

No animal or iPSC models of RNU4-2 or RNU6 RP have been reported.
Only functional model so far: ectopic expression of tagged mutant snRNA in cultured cells, followed by co-IP (in vitro; cell line not named in the preprint).
Related models that could serve as proxies, with caveats:
Prpf31 mouse models show weak retinal phenotypes. This is a known human–model mismatch, and a HUMAN_MODEL_MISMATCH discussion would be appropriate.
PRPF31 patient iPSC-derived RPE cells and retinal organoids do recapitulate splicing-factor RP. Equivalent organoids carrying snRNA variants would be the natural next model.
Practical difficulty: RNU6 is multi-copy, so engineering one paralog is hard to do in mouse. Mouse U6 gene organisation differs from human, which is a species-mismatch caveat.

Notes for KB curation

Name the disease as an allelic-but-distinct entity from ReNU syndrome. If MONDO has no term, record that and do not reuse the ReNU or generic RP term as an exact match.
Use the published paper (PMID:41513982) as the primary citation and the preprint (PMID:39830270) for detail. Fetch both with just fetch-reference and quote only text that is in the cache. The full text is in PMC for the preprint, so detailed snippets may need a --force full-text fetch.
The mechanism nodes after step 4 are inferences. Tag them with directness: INDIRECT, or put them under a mechanistic_hypotheses entry with status: EMERGING.
Classify the evidence:
co-IP: IN_VITRO;
structural mapping: COMPUTATIONAL;
cohort and family data: HUMAN_CLINICAL.
Bind the inheritance terms HP:0000006 (autosomal dominant) and HP:0003829 (incomplete penetrance). Verify both, as with every CURIE in this report.

Sources

Quinodoz M, et al. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat Genet 2026;58:169–179. PMID:41513982. DOI · NLK record · UCL Discovery OA · HUJI CRIS · Oxford ORA · BIDMC · UTHealth
Quinodoz M, et al. De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa. medRxiv 2025. PMID:39830270, PMC11741465 · NLK record
Genomics England PanelApp, Retinal disorders (panel 307): RNU6-1, RNU6-2, RNU6-8, RNU6-9
PanelApp Australia: RNU6-1, panel 137 · RNU6-1, RP panel 277
News coverage, January 2026: News-Medical (1) · News-Medical (2) · Eyefox / IOB
Institutional repository records: Università della Campania · Università di Parma

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	4
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	4
On topic	3
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	33
Resolved	32
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	1
Terms whose name is worth a second look	2

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:

GO:0045494 (1 mention) - the report calls it "expected `DECREASED"; GO calls it photoreceptor cell maintenance

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:0000006 (2 mentions) - the report calls it "Inheritance: autosomal dominant", "autosomal dominant"; HP calls it Autosomal dominant inheritance**, and lists "Autosomal dominant" among its other names
HP:0003829 (1 mention) - the report calls it "incomplete penetrance"; HP calls it Typified by incomplete penetrance, and lists "Incomplete penetrance" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0000006 - called "Inheritance:** autosomal dominant", "autosomal dominant"

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.

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References & Deep Research

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U4 and U6 snRNA Gene-Related Retinitis Pigmentosa: Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

Pathogenic variants

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain

7. Anatomical Structures

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species

15. Model Organisms

Notes for KB curation

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver