Affinage

RNPC3

RNA-binding region-containing protein 3 · UniProt Q96LT9

Length
517 aa
Mass
58.6 kDa
Annotated
2026-06-10
10 papers in source corpus 6 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNPC3 encodes the U11/U12-65K protein, an essential and unique component of the minor (U12-dependent) spliceosome required for excision of U12-type introns from a small subset of genes (PMID:30254136). It is a nuclear protein containing two RNA recognition motifs and two bipartite nuclear targeting sequences (PMID:14974681), and functions as a molecular bridge promoting formation of the U11/U12 di-snRNP within the minor spliceosome (PMID:41946577). Across mammalian tissues RNPC3-dependent minor intron splicing is developmentally indispensable: germline loss causes pre-implantation embryonic lethality (PMID:30254136), conditional ablation in intestinal epithelium increases U12-type intron retention with loss of phospho-ERK1/2 signaling, reduced proliferation, and increased apoptosis (PMID:30254136), a pathogenic RRM2-domain variant impairs pituitary growth-hormone content (PMID:34906446), and B-cell-specific ablation impairs germinal center responses through retention of minor introns in proliferation- and apoptosis-associated genes (PMID:40170400). Beyond its splicing role, RNPC3 physically interacts with the HDAC3 cofactor ANKRD11, which bridges synergistic chromatin co-binding of RNPC3 and HDAC3 and couples minor spliceosome activity to H3K9 histone deacetylation and transcriptional regulation (PMID:38837887).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2003 Medium

    Established the basic molecular identity and subcellular address of the RNPC3 protein, defining it as a nuclear RNA-binding protein.

    Evidence cDNA cloning, sequence analysis, and GFP fusion localization imaging

    PMID:14974681

    Open questions at the time
    • No functional role in splicing demonstrated
    • RRM RNA targets not identified
    • No mutagenesis of nuclear targeting sequences
  2. 2010 Low

    Framed RNPC3 mechanistically as a bridging factor for U11/U12 di-snRNP assembly within the minor spliceosome.

    Evidence Cited as established background in a clinical autoantibody report; no primary experiment in the available abstract

    PMID:41946577

    Open questions at the time
    • Original experimental source not present in corpus
    • No structural model of the bridging interaction provided here
    • RNA contacts mediating di-snRNP formation undefined
  3. 2018 High

    Demonstrated in vivo that RNPC3 is required for U12-type intron excision and that its loss is incompatible with early development, linking minor splicing to organismal viability and tissue homeostasis.

    Evidence Germline and conditional Rnpc3 knockout mice with RT-PCR intron retention assays, phospho-ERK1/2 immunostaining, and proliferation/apoptosis assays in intestinal epithelium

    PMID:30254136

    Open questions at the time
    • Mechanistic link between intron retention and ERK signaling is correlative
    • Specific minor-intron-containing transcripts driving the phenotype not fully resolved
    • Does not address splicing-independent functions
  4. 2021 Medium

    Connected RNPC3 to pituitary and forebrain development and showed a disease-associated RRM2 variant produces a defined endocrine phenotype.

    Evidence In situ hybridization on mouse/human embryos and CRISPR/Cas9 p.Leu483Phe knock-in mice with pituitary GH content measurement

    PMID:34906446

    Open questions at the time
    • Splicing defects underlying the GH phenotype not directly mapped
    • Single variant tested
    • Sex-specific effect mechanism unexplained
  5. 2024 High

    Uncovered a chromatin-coupled function: RNPC3 physically associates with ANKRD11/HDAC3 and links minor spliceosome activity to histone deacetylation and transcription.

    Evidence Affinity purification, CRISPR deletion strains, domain mapping, CUT&Tag, and ANKRD11 knockdown with H3K9 deacetylation readout, plus Drosophila 65K deletion with histone deacetylation and neural phenotyping

    PMID:38837887

    Open questions at the time
    • Whether chromatin co-binding requires catalytic splicing activity is unresolved
    • Direct genomic targets co-regulated by RNPC3 and HDAC3 not enumerated
    • Mechanism by which a spliceosomal RRM protein engages chromatin undefined
  6. 2025 High

    Extended the requirement for RNPC3-dependent minor splicing to adaptive immunity, showing it sustains germinal center B cell proliferation and survival.

    Evidence B-cell-specific conditional Rnpc3 knockout mice with flow cytometry, proliferation/apoptosis assays, and minor intron retention analysis

    PMID:40170400

    Open questions at the time
    • Individual causal minor-intron-containing genes not isolated
    • Relationship to the ANKRD11/HDAC3 axis in B cells untested
    • Effect on antibody affinity maturation outcome not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNPC3's role in di-snRNP assembly mechanistically integrates with its chromatin/HDAC3-coupled transcriptional function across tissues remains unresolved.
  • No structure of the U11/U12-65K bridging interaction in the corpus
  • Whether splicing and chromatin functions are separable is untested
  • Tissue-specific minor-intron target sets driving distinct phenotypes not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-4839726 Chromatin organization 1
Partners
ANKRD11HDAC3
Complex memberships
U11/U12 di-snRNPminor (U12-dependent) spliceosome

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RNPC3 encodes a protein with two RNA recognition motif (RRM) domains and two bipartite nuclear targeting sequences; GFP localization experiments demonstrated that the RNPC3 protein localizes to the cell nucleus. cDNA cloning, sequence analysis, GFP fusion localization imaging Biochemical genetics Medium 14974681
2018 RNPC3 (encoding the U11/U12-65K protein) is an essential component of the U12-dependent (minor class) spliceosome; conditional knockout of Rnpc3 in adult mice caused increased retention of U12-type introns in intestinal epithelial cell transcripts, demonstrating that 65K is required for minor intron splicing in vivo. Conditional Rnpc3 knockout mouse model, RT-PCR for U12 intron retention in purified intestinal epithelial cells RNA (New York, N.Y.) High 30254136
2018 Loss of Rnpc3 in intestinal stem/progenitor cells leads to loss of phospho-ERK1/2 signaling, reduced proliferation, and increased apoptosis, placing U12-dependent splicing upstream of ERK signaling in intestinal homeostasis. Conditional Rnpc3 knockout mouse, immunostaining for phospho-ERK1/2, cell proliferation and death assays in intestinal crypts RNA (New York, N.Y.) Medium 30254136
2018 Homozygous Rnpc3 null mice die prior to blastocyst implantation, establishing that 65K/RNPC3-mediated U12 splicing is essential for the earliest stages of mammalian embryonic development. Germline Rnpc3 knockout mouse, developmental stage analysis RNA (New York, N.Y.) High 30254136
2021 RNPC3 is expressed in the developing forebrain, including the hypothalamus and Rathke's pouch (the pituitary anlage), in both mouse and human embryos; CRISPR/Cas9 knock-in of the p.Leu483Phe pathogenic variant in the Rnpc3 RRM2 domain in female mice reduced pituitary GH content, establishing a developmental role for RNPC3 in pituitary function. In situ hybridization on murine/human embryonic sections, CRISPR/Cas9 knock-in mouse model, pituitary GH content measurement Genetics in medicine : official journal of the American College of Medical Genetics Medium 34906446
2024 The minor spliceosomal 65K/RNPC3 protein physically interacts with ANKRD11, a cofactor of histone deacetylase 3 (HDAC3); in human cells, the ANKRD11 middle uncharacterized domain mediates the association of Hs65K with HDAC3. ANKRD11 acts as a bridging factor enabling synergistic chromatin co-binding of HDAC3 and Hs65K, and knockdown of ANKRD11 reduces their common chromatin binding and decreases H3K9 deacetylation at nearby loci, linking minor spliceosome activity to histone deacetylation and transcriptional regulation. Affinity purification from Drosophila lysates, CRISPR/Cas9 deletion strains, CUT&Tag chromatin binding assay, ANKRD11 knockdown with H3K9 deacetylation measurement, domain mapping Advanced science (Weinheim, Baden-Wurttemberg, Germany) High 38837887
2024 Loss of 65K/RNPC3 in Drosophila (Dm65KΔ/Δ) caused reduced histone deacetylation at H3K9 and H4K5 in heads and neural-related defects, functionally linking the minor spliceosome component to histone deacetylase activity in vivo. CRISPR/Cas9 deletion in Drosophila, histone deacetylation assays, neural phenotype characterization Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38837887
2025 Conditional ablation of RNPC3 in activated B cells impaired germinal center (GC) B cell development, inhibited proliferation, and promoted apoptosis; mechanistically, RNPC3 deficiency caused accumulation of minor intron retention in minor intron-containing genes associated with cell proliferation and apoptosis, establishing that RNPC3-dependent minor intron splicing is required for the GC B cell response. Conditional B-cell-specific Rnpc3 knockout mice, flow cytometry for GC B cell populations, proliferation and apoptosis assays, minor intron retention analysis European journal of immunology High 40170400
2010 RNPC3 protein acts as a molecular bridge promoting U11/U12 RNP (di-snRNP) complex formation within the minor spliceosome. Reported as established function in autoantibody clinical literature (referenced as prior mechanistic knowledge) ACR open rheumatology Low 41946577

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency. American journal of medical genetics. Part A 24 32462814
2018 Early developmental arrest and impaired gastrointestinal homeostasis in U12-dependent splicing-defective Rnpc3-deficient mice. RNA (New York, N.Y.) 22 30254136
2021 Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency. Genetics in medicine : official journal of the American College of Medical Genetics 11 34906446
2019 Identification of RNPC3 as a novel JAK2 fusion partner gene in B-acute lymphoblastic leukemia refractory to combination therapy including ruxolitinib. Molecular genetics & genomic medicine 11 31885183
2024 Minor Spliceosomal 65K/RNPC3 Interacts with ANKRD11 and Mediates HDAC3-Regulated Histone Deacetylation and Transcription. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 9 38837887
2003 Cloning and identification of a novel human RNPC3 gene that encodes a protein with two RRM domains and is expressed in the cell nucleus. Biochemical genetics 8 14974681
2021 Establishing intellectual disability as the key feature of patients with biallelic RNPC3 variants. American journal of medical genetics. Part A 6 33650182
2023 A Novel RNPC3 Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy. Hormone research in paediatrics 3 37463572
2025 Minor Splicing Factor RNPC3 Is Essential for the Germinal Center B Cell Response. European journal of immunology 2 40170400
2026 Clinical Associations of Anti-RNPC3 Autoantibodies in Mixed Connective Tissue Disease. ACR open rheumatology 0 41946577

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