This is a mechanism module, not a disease, and conformance is node-level consistency rather than inheritance. Scope: germline variants in genes encoding spliceosomal snRNAs or core spliceosome proteins. Exclude variants that mis-splice only their own transcript, which belong on that gene's entry and, where a splice-switching drug exists, under antisense_oligonucleotide_therapy. Exclude somatic splicing-factor mutations in myeloid neoplasms (SF3B1, SRSF2, U2AF1, ZRSR2), which are change-of-function clonal drivers with a different downstream chain. Exclude defects in snRNP assembly upstream of the spliceosome, such as SMN deficiency in spinal muscular atrophy, unless the entry argues that the splicing step is its operative mechanism. Two classes of trigger are covered and conforming entries should say which applies. Most protein-gene disorders are haploinsufficient (SF3B4, EFTUD2, TXNL4A, PRPF31). Dominant snRNA variants (RNU4-2, RNU5B-1) cluster in a few nucleotides of one structural element and may act by altered function or dominant-negative effect rather than by loss; whether they are degraded by snRNA quality control is an open question recorded on those entries. The p53 node is a branch, not a step every conformer must have. It is established for EFTUD2 in neural crest, where Mdm2 exon skipping raises P53, but deleting Trp53 in those cells did not rescue craniofacial development, so p53 activation is a contributor rather than the whole explanation. Retinal conformers such as PRPF31 retinopathy go from mis-splicing to photoreceptor and RPE dysfunction without it. Which transcripts in a given cell type explain the phenotype is not settled for most conformers and should be cited per entry, never inherited from this module.
Why does a defect in the ubiquitous spliceosome fail only certain cell types, and differently by gene?
KNOWLEDGE GAP
OPEN
spliceosomopathy_tissue_specificity
Attached to:
Failure of Splicing-Sensitive Cell Populations
Craniofacial spliceosomopathies hit cranial neural crest, PRPF-gene disorders hit the retina, and snRNA-gene disorders hit the developing brain. Candidate explanations include higher splicing demand at a critical developmental window, dosage thresholds that only some cells cross, and cell-type-specific sensitive transcripts such as MDM2 in neural crest. The Trp53 non-rescue in Eftud2 neural crest shows the known stress pathway is not sufficient, and no study has compared the same spliceosome defect across cell types side by side.
Germline Spliceosome Component Variant
trigger
A germline variant reduces the dosage of, or alters the sequence of, an RNA or protein component of the major or minor spliceosome.
Used by disorders
ReNU Syndrome
as RNU4-2 Critical-Region Variant Disrupts U4 snRNA / Spliceosome Function
Downstream
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Mis-Splicing of a Sensitive Transcript Subset
Show evidence (2 references)
"Spliceosomal syndromes are a group of disorders caused by pathogenic variants in core spliceosomal RNAs or proteins, leading to defective pre-mRNA splicing and tissue-specific disease vulnerability."
Defines the disease class and its trigger.
"Genetic variants affecting the function of several core splicing factors, namely SF3B4, SF3B2, EFTUD2, SNRPB and TXNL4A, are responsible for MFD in five related but distinct syndromes"
Names the core splicing-factor genes behind the craniofacial spliceosomopathies.
Mis-Splicing of a Sensitive Transcript Subset
central effector
Reduced or altered spliceosome function changes the splicing of a subset of transcripts, most often as increased exon skipping or shifted alternative splice-site use, rather than abolishing splicing globally. The affected set differs by gene, variant and cell type.
Downstream
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P53 Activation via MDM2 Exon Skipping
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Failure of Splicing-Sensitive Cell Populations
Show evidence (2 references)
"Temporal RNA-sequencing analyses of mutant embryos identified an increase in exon-skipping events, followed by important transcriptional changes associated with an enrichment for terms consistent with defects in NC cell migration and survival."
Exon skipping precedes the transcriptional changes in the sf3b4 mutant frog.
"Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes."
In PRPF31 retinopathy the defect is in specific splicing programmes, not all splicing.
P53 Activation via MDM2 Exon Skipping
amplifier
In neural crest, skipping of MDM2 exon 3 lowers functional MDM2, raising nuclear P53 and P53 target expression and increasing cell death. Shown for EFTUD2; deleting Trp53 reduces apoptosis without rescuing craniofacial development, so this is a contributing branch.
Downstream
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Failure of Splicing-Sensitive Cell Populations
Show evidence (3 references)
"RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3."
Identifies the Mdm2 exon-skipping event in Eftud2 mutant neural crest.
"Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death."
Links the mis-splicing to P53 activation and cell death.
"brain and craniofacial development, and survival were not improved in double mutant embryos"
Refutes P53 activation as the sole cause of the craniofacial defect: removing Trp53 in neural crest did not rescue development.
Failure of Splicing-Sensitive Cell Populations
effector
Cells with high splicing demand at a critical stage fail or die. In the craniofacial spliceosomopathies this is early depletion of cranial neural crest progenitors; in PRPF31 retinopathy it is retinal pigment epithelium dysfunction and rod photoreceptor death. A conforming entry substitutes its own cell type.
Downstream
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Tissue-Restricted Disease from a Ubiquitous Machine
Show evidence (2 references)
"Animal models of NRS and MFDM indicate that MFD results from an early depletion of neural crest progenitors through a mechanism that involves apoptosis."
Neural crest progenitor loss is the craniofacial instance of this node.
"PRPF31-mutated retinal organoids recapitulate the human RP phenotype, with a rod photoreceptor cell death followed by a loss of cones."
Rod photoreceptor death is the retinal instance of this node.
Tissue-Restricted Disease from a Ubiquitous Machine
consequence
The clinical phenotype is confined to the tissues whose precursor cells failed: facial dysostosis, retinal degeneration, or neurodevelopmental disease, despite the spliceosome working in every cell.
Show evidence (2 references)
"An outstanding question in the field is how mutations in the ubiquitously expressed spliceosome lead to such cell- and tissue-specific disorders."
States the tissue-specificity of the outcome and that its cause is open.
"Although the spliceosome is ubiquitously expressed, its dysfunction preferentially affects highly splicing-dependent tissues such as the retina and the nervous system."
Names retina and nervous system as the preferentially affected tissues.