Affinage

RSPH4A

Radial spoke head protein 4 homolog A · UniProt Q5TD94

Length
716 aa
Mass
80.7 kDa
Annotated
2026-06-10
12 papers in source corpus 5 papers cited in narrative 5 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

RSPH4A encodes a structural component of the axonemal radial spoke head required for normal motility of 9+2 motile cilia, and its loss causes primary ciliary dyskinesia (PMID:19200523). RSPH4A builds the distal head architecture of radial spokes: in human respiratory cilia its loss eliminates the radial spoke heads of RS1 and RS2 (but spares RS3) and produces additional defects in the arch domains adjacent to those heads, with secondary heterogeneous abnormalities of the central pair complex (PMID:33852348). In mouse tracheal cilia Rsph4a is required for assembly of all three radial spoke heads (RS1, RS2, RS3), and it supports planar ciliary beating across tracheal, ependymal, and oviduct epithelia (PMID:32203505). Loss-of-function mutations, including a splice-site allele generating premature termination, abolish this function and yield central-apparatus ultrastructural defects, reduced beat frequency, and abnormal waveform (PMID:19200523, PMID:23798057); correction of the RSPH4A sequence in patient-derived cells partially restores normal ciliary motion (PMID:42050778).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2009 High

    Established RSPH4A as a radial spoke head gene whose loss-of-function mutations cause primary ciliary dyskinesia, defining a genetic basis for central-pair-associated ciliary dysmotility.

    Evidence SNP linkage, positional candidate identification, and human mutation analysis with ortholog functional context

    PMID:19200523

    Open questions at the time
    • Did not resolve which radial spoke heads RSPH4A builds at structural resolution
    • Mechanism linking radial spoke loss to central pair abnormality not defined
  2. 2013 Medium

    Showed that a specific splice-site mutation causes premature termination and loss of function, linking RSPH4A sequence disruption to measurable ciliary ultrastructural and motility defects.

    Evidence Genetic sequencing, transcript analysis, electron microscopy, beat frequency and waveform measurement in patient cilia

    PMID:23798057

    Open questions at the time
    • Single study; structural localization of the defect within radial spokes not resolved
    • Protein-level consequence inferred from transcript, not directly visualized
  3. 2020 High

    Defined the structural role of Rsph4a in vivo by showing it is required to assemble all three radial spoke heads and to support planar beating across multiple ciliated epithelia in mouse.

    Evidence Cryo-electron tomography of knockout mouse tracheal cilia with ciliary movement and immunofluorescence readouts

    PMID:32203505

    Open questions at the time
    • Mouse three-head requirement differs from later human findings; species-specific architecture unresolved
    • Does not establish direct protein-protein contacts within the spoke head
  4. 2021 High

    Pinpointed the human structural defect to absence of RS1 and RS2 spoke heads (sparing RS3) plus adjacent arch domain defects, distinguishing RSPH4A loss from RSPH1 loss and revealing secondary central pair abnormalities.

    Evidence Cryo-ET with subtomogram averaging of patient-derived human respiratory cilia versus controls and RSPH1-/- cilia

    PMID:33852348

    Open questions at the time
    • Mechanism by which spoke head loss secondarily perturbs the central pair not defined
    • Atomic-resolution position of RSPH4A within the spoke head head not determined
  5. 2026 Medium

    Demonstrated that correcting the RSPH4A sequence is sufficient to restore ciliary function, providing causal confirmation that the motility defect stems from the gene lesion.

    Evidence AAV-mediated adenosine base editing of patient-derived cells with Western blot, digital PCR, and high-speed/confocal microscopy of ciliary motion

    PMID:42050778

    Open questions at the time
    • Single proof-of-concept study with limited editing efficiency and partial (~30%) functional rescue
    • Does not show restoration of radial spoke head ultrastructure

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism by which loss of RS1/RS2 spoke heads secondarily destabilizes the central pair complex, and the molecular contacts RSPH4A makes within the spoke head, remain unresolved.
  • No atomic-resolution model of RSPH4A within the spoke head
  • Direct binding partners of RSPH4A in the spoke head not biochemically defined
  • Basis of species difference (three heads in mouse vs RS1/RS2 in human) unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2
Complex memberships
radial spoke head

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 RSPH4A encodes a protein component of the axonemal radial spoke head; loss-of-function mutations cause primary ciliary dyskinesia with central-microtubular-pair abnormalities (intermittent or complete absence of the central pair), establishing its role in maintaining normal motile cilia movement in 9+2-structure cilia and flagella. SNP-based linkage analysis, positional candidate gene identification, in situ hybridization (murine Rsph9), zebrafish knockdown/rescue experiments for RSPH9 ortholog (functional context for radial spoke head proteins), human mutation analysis American journal of human genetics High 19200523
2020 Rsph4a is required for assembly of all three radial spoke heads (RS1, RS2, and RS3) in mouse tracheal cilia; Rsph4a-deficient mice lack all triplet spoke heads as revealed by cryo-electron tomography, and Rsph4a contributes to planar beating of motile cilia in trachea, ependymal tissue, and oviduct by building the distal architecture of radial spokes. Cryo-electron tomography of Rsph4a-knockout mouse tracheal cilia, ciliary movement observation, immunofluorescence analysis PLoS genetics High 32203505
2021 In RSPH4A-/- human respiratory cilia, the radial spoke heads of RS1 and RS2 (but not RS3) are missing, and there are additional defects in the arch domains adjacent to RS1 and RS2 heads (distinct from RSPH1-/- defects); secondary heterogeneous defects in the central pair complex are also observed, establishing the specific structural role of RSPH4A at RS1 and RS2 spoke heads and adjacent arch domains. Cryo-electron tomography (cryo-ET) and subtomogram averaging of noninvasively collected human PCD patient respiratory cilia compared to controls Molecular biology of the cell High 33852348
2013 A splice-site mutation (c.921+3_6delAAGT) in RSPH4A leads to a premature translation termination signal and loss of function, confirmed by quantitative ciliary ultrastructural analysis showing central apparatus defects, reduced ciliary beat frequency and abnormal waveform, and transcript analysis. Genetic sequencing, transcript analysis, ciliary ultrastructural analysis by electron microscopy, measurement of ciliary beat frequency and waveform Human mutation Medium 23798057
2026 AAV-mediated adenosine base editing targeting RSPH4A mutations in patient-derived cells partially restored normal ciliary motion pattern (~30.4% increase in normal motion pattern with reduction in circular motions) demonstrating that correction of RSPH4A sequence restores ciliary function. AAV-mediated base editing (nickase Cas9 fused to adenosine deaminase), Western blot, digital PCR for editing efficiency, high-speed video and confocal microscopy for ciliary beat frequency and motion pattern in patient cells Human gene therapy Medium 42050778

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. American journal of human genetics 271 19200523
2013 Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Human mutation 52 23798057
2020 Rsph4a is essential for the triplet radial spoke head assembly of the mouse motile cilia. PLoS genetics 31 32203505
2023 The RSPH4A Gene in Primary Ciliary Dyskinesia. International journal of molecular sciences 18 36768259
2021 Primary Ciliary Dyskinesia Diagnostic Challenges: Understanding the Clinical Phenotype of the Puerto Rican RSPH4A Founder Mutation. Diagnostics (Basel, Switzerland) 17 33670432
2021 Structural insights into the cause of human RSPH4A primary ciliary dyskinesia. Molecular biology of the cell 16 33852348
2021 Primary Ciliary Dyskinesia: Ancestral Haplotypes Analysis of the RSPH4A Founder Mutation in Puerto Rico. Cureus 4 34513534
2025 Assessing Olfactory Acuity in Primary Ciliary Dyskinesia with the RSPH4A Founder Mutation. Journal of clinical medicine 2 40429607
2025 Primary ciliary dyskinesia in a Japanese woman caused by a novel RSPH4A variant. Respiratory investigation 1 40262389
2024 A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review. Frontiers in genetics 1 38818043
2026 AAV-Mediated Base Editing for Correction of RSPH4A Mutations in Primary Ciliary Dyskinesia: A Proof-of-Concept Study. Human gene therapy 0 42050778
2025 Analysis of clinical and genetic features in an adolescent patient with primary ciliary dyskinesia induced by homozygous mutation in the RSPH4A gene: a case report. Frontiers in pediatrics 0 40852414

Missed literature

Know a paper Affinage missed for RSPH4A? Flag it for the maintainers and the community.

No submissions yet.