Affinage

RSPH1

Radial spoke head 1 homolog · UniProt Q8WYR4

Length
309 aa
Mass
35.1 kDa
Annotated
2026-04-28
36 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPH1 is a structural component of the radial spoke head in 9+2 motile cilia and sperm flagella, essential for proper ciliary waveform and central pair microtubule stability. RSPH1 localizes to the radial spoke heads of RS1 and RS2 (but not RS3), where it functions downstream of the core head protein RSPH4A and is required for recruitment of RSPH9, establishing a defined assembly hierarchy within the radial spoke head (PMID:25789548, PMID:33852348). Loss of RSPH1 does not abolish ciliary beat frequency but converts normal planar beating into an abnormal circular waveform, destabilizes central pair microtubules, and causes primary ciliary dyskinesia as well as male infertility due to sperm dysmotility (PMID:24568568, PMID:36873931, PMID:23993197). In sperm flagella, RSPH1 participates in a cytoplasmic pre-assembly complex with CFAP65 and MNS1 and interacts with axonemal partners including CCDC189 and DNAH12 that contribute to central pair integrity (PMID:34231842, PMID:37601242).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2005 Medium

    Initial localization of the RSPH1 ortholog (Tsga2) to sperm tail structures and genetic association with the 'curlicue' flagellar waveform defect in t-complex mice established RSPH1 as a candidate flagellar function gene.

    Evidence Protein localization and genetic mapping in heterospecific t-complex mouse sperm

    PMID:16354795

    Open questions at the time
    • No direct loss-of-function model for Tsga2 was generated
    • Acrosomal localization was uncertain
    • Mechanism linking t-allele mutations to waveform defect was not determined
  2. 2007 High

    EM immunocytochemistry placed RSPH1 within the radial spoke structures of the axoneme across multiple ciliated and flagellated cell types, establishing it as a bona fide radial spoke component.

    Evidence EM immunocytochemistry and immunofluorescence of human sperm, tracheal, and ependymal cilia

    PMID:17451891

    Open questions at the time
    • Precise position within radial spoke (head vs. stalk) was not resolved
    • Functional consequence of RSPH1 loss was unknown
  3. 2013 High

    Identification of loss-of-function RSPH1 mutations as a cause of primary ciliary dyskinesia with central complex and radial spoke defects demonstrated that RSPH1 is essential for motile cilia function in humans.

    Evidence Homozygosity mapping, exome sequencing, and immunofluorescence in airway cells from multiple PCD families

    PMID:23993197

    Open questions at the time
    • Whether the central pair defect was a direct or secondary consequence of radial spoke head loss was unresolved
    • The specific structural role within the RS head was not defined
  4. 2014 High

    Functional analysis of RSPH1-mutant cilia revealed that loss of RSPH1 abolishes normal planar waveform without reducing beat frequency, separating waveform regulation from beat generation and showing that RSPH1 mutations additionally cause loss of RSPH4A and RSPH9 from the axoneme.

    Evidence High-speed videomicroscopy and high-resolution immunofluorescence of nasal/airway cilia from RSPH1-mutant patients across multiple families

    PMID:24518672 PMID:24568568

    Open questions at the time
    • Whether RSPH1 directly stabilizes RSPH4A or vice versa was ambiguous from immunofluorescence alone
    • Structural basis for central pair instability remained unresolved
  5. 2015 High

    Systematic comparison of RSPH4A-, RSPH1-, and RSPH9-mutant cilia established a linear assembly hierarchy — RSPH4A recruits RSPH1, which in turn recruits RSPH9 — defining RSPH1's position in radial spoke head biogenesis.

    Evidence High-resolution immunofluorescence across 16 PCD families with defined genotypes in RSPH4A, RSPH1, and RSPH9

    PMID:25789548

    Open questions at the time
    • Direct protein–protein interactions underpinning the hierarchy were not biochemically demonstrated
    • Whether RSPH3 stalk protein physically contacts RSPH1 was unclear
  6. 2021 High

    Cryo-electron tomography resolved the structural impact of RSPH1 loss to the heads of RS1 and RS2 specifically (not RS3), and distinguished RSPH1's contribution from RSPH4A's by showing that RSPH4A loss additionally disrupts arch domains adjacent to RS heads.

    Evidence Cryo-ET and subtomogram averaging of RSPH1−/− and RSPH4A−/− patient respiratory cilia at nanometer resolution

    PMID:33852348

    Open questions at the time
    • Atomic-resolution structure of RSPH1 within the RS head was not obtained
    • The identity of the arch-domain components lost in RSPH4A but not RSPH1 mutants was unknown
  7. 2021 Medium

    Co-immunoprecipitation revealed that RSPH1 participates in a cytoplasmic pre-assembly complex with CFAP65, MNS1, and other proteins during spermiogenesis, and that CFAP206 is required for RSPH1 localization to the sperm axoneme, identifying upstream assembly factors.

    Evidence Endogenous Co-IP in mouse testes (CFAP65 network) and immunostaining of CFAP206-deficient patient sperm

    PMID:34231842 PMID:34255152

    Open questions at the time
    • RSPH1-CFAP65 interaction was shown by single Co-IP without reciprocal validation
    • Whether the cytoplasmic complex is a general RS pre-assembly intermediate or spermiogenesis-specific was not tested
    • The mechanism by which CFAP206 enables RSPH1 docking was not determined
  8. 2023 High

    RSPH1 mutations were shown to cause male infertility via sperm flagellar dysmotility, and RSPH1 was identified as an axonemal interaction partner of CCDC189, expanding RSPH1's known functional context from respiratory cilia to fertility.

    Evidence Immunofluorescence and high-speed video of RSPH1-mutant sperm; Co-IP and mass spectrometry of CCDC189 interactors in mouse sperm

    PMID:36873931 PMID:37601242

    Open questions at the time
    • Whether RSPH1–CCDC189 interaction is direct or bridged was not established
    • Structural basis of flagellar versus ciliary phenotypic differences in RSPH1 mutants was not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The atomic-resolution structure of RSPH1 within the radial spoke head, its direct binding interfaces with RSPH4A and RSPH9, and the mechanism by which radial spoke head integrity stabilizes the central pair remain to be determined.
  • No high-resolution (cryo-EM/crystal) structure of RSPH1 or the RS head complex exists
  • Direct protein–protein interaction surfaces between RSPH1 and RSPH4A/RSPH9 have not been mapped
  • The mechanotransduction pathway by which radial spoke heads regulate ciliary waveform planarity is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
CCDC189CFAP206CFAP65MNS1RSPH4ARSPH9
Complex memberships
Radial spoke head (RS1/RS2)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RSPH1 (human meichroacidin/RSP44) protein localizes within the radial spokes of the axonemal complex of sperm flagella and in cilia of tracheal and ependymal epithelial cells, as determined by EM immunocytochemistry and immunofluorescence, establishing it as a radial spoke structural component. EM immunocytochemistry, immunofluorescence, Western blot, Northern blot Gene High 17451891
2013 Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects; wild-type RSPH1 localizes within cilia of airway cells but is undetectable in cilia from individuals with RSPH1 loss-of-function mutations, demonstrating RSPH1 is required for proper assembly of central complexes and radial spokes in human airway cilia. Homozygosity mapping, whole-exome sequencing, immunofluorescence localization in airway cells, high-speed videomicroscopy American journal of human genetics High 23993197
2014 RSPH1 mutations cause loss of RSPH4A and RSPH9 from mutant cilia by high-resolution immunofluorescence, suggesting RSPH1 is required for assembly of the entire radial spoke head structure; central pair microtubule loss in RSPH1-mutant cilia is proposed to result from instability due to loss of radial spoke head tethering. Targeted NGS panel, high-resolution immunofluorescence, ultrastructural analysis (TEM) Human molecular genetics High 24518672
2014 Biallelic loss-of-function mutations in RSPH1 cause PCD with a unique phenotype: cilia exhibit normal beat frequency but an abnormal circular beat pattern, indicating RSPH1 is required for normal ciliary waveform rather than beat frequency per se. Exome sequencing, Sanger sequencing, high-speed videomicroscopy of nasal cilia American journal of respiratory and critical care medicine High 24568568
2015 Immunofluorescence analysis of human respiratory cilia showed that absence of RSPH4A results in deficient axonemal assembly of both RSPH1 and RSPH9; RSPH1 mutant cilia lacking RSPH1 fail to assemble RSPH9; whereas RSPH9 mutations result in absence of RSPH9 but do not affect RSPH1 or RSPH4A assembly. This establishes an assembly hierarchy: RSPH4A is the core RS head protein, RSPH1 is required downstream for RSPH9 recruitment. High-resolution immunofluorescence analysis of human respiratory cilia from PCD patients with defined mutations American journal of respiratory cell and molecular biology High 25789548
2015 RSPH3 mutations result in near absence of radial spokes but RSPH1 and RSPH4A (RS head proteins) remain present within cilia, placing RSPH3 (RS stalk) upstream of RS head assembly including RSPH1 in the radial spoke assembly pathway. Immunofluorescence of airway cells from RSPH3-mutant individuals, high-speed videomicroscopy, TEM American journal of human genetics Medium 26073779
2021 Cryo-electron tomography of RSPH4A-/- human respiratory cilia revealed that radial spoke heads of RS1 and RS2 (but not RS3) are missing, similarly to RSPH1-/- cilia, but RSPH4A-/- cilia additionally show defects in arch domains adjacent to RS1 and RS2 heads not seen with RSPH1 loss, structurally distinguishing the contributions of RSPH4A and RSPH1 to the radial spoke head. Cryo-electron tomography (cryo-ET) and subtomogram averaging of patient cilia Molecular biology of the cell High 33852348
2021 CFAP65 forms a cytoplasmic protein network with MNS1, RSPH1, TPPP2, ZPBP1 and SPACA1 during spermiogenesis, as shown by endogenous co-immunoprecipitation and immunostaining in mouse testes, suggesting RSPH1 participates in a cytoplasmic complex prior to axonemal incorporation. Endogenous co-immunoprecipitation, immunostaining, Cfap65 knockout mouse model Human molecular genetics Medium 34231842
2021 In a CFAP206-deficient patient, immunostaining of sperm cells demonstrated absence of both WDR66 and RSPH1 proteins, indicating that CFAP206 (a microtubule-docking adapter for radial spoke and inner dynein arm) is required for RSPH1 localization to the sperm flagellum axoneme. Immunostaining of patient sperm cells, CRISPR-Cas9 Cfap206 KO mouse model Human genetics Medium 34255152
2023 Pathogenic variants in RSPH1 cause male infertility due to sperm cell dysmotility and abnormal flagellar RSPH1 composition, demonstrated by immunofluorescence microscopy of sperm flagella from infertile men with RSPH1 mutations; this is the first direct demonstration that RSPH1 variants cause male infertility via flagellar dysfunction. Immunofluorescence microscopy of sperm flagella, high-speed video microscopy, TEM, NGS Frontiers in genetics High 36873931
2023 CCDC189 (a radial-spoke-associated protein) interacts with RSPH1 in sperm axoneme, as demonstrated by co-immunoprecipitation and mass spectrometry, and inactivation of CCDC189 causes downregulation of both CABCOCO1 and indirectly involves RSPH1 in sperm flagellum formation. Co-immunoprecipitation, mass spectrometry, immunoelectron microscopy, Ccdc189 knockout mouse National science review Medium 37601242
2024 DNAH12 interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate central pair stability in sperm flagella, as demonstrated by co-immunoprecipitation; DNAH12 deficiency leads to central pair loss in sperm but not cilia, placing RSPH1 in a DNAH12-dependent pathway for CP stability. Co-immunoprecipitation, Dnah12 knockout and knockin mouse models, TEM, immunofluorescence bioRxivpreprint Medium bio_10.1101_2024.06.20.599934
2011 RSPH1 (TSGA2) was identified as a 14-3-3 binding protein in testis by tandem affinity purification followed by LC-MS/MS, suggesting RSPH1 participates in 14-3-3-regulated signaling during spermatogenesis. Tandem affinity purification (TAP) with transgenic 14-3-3ζ mice, LC-MS/MS Spermatogenesis Low 22332119
2005 TSGA2 (mouse ortholog of RSPH1) polypeptides localize to major sperm tail structures and apparently to the vicinity of the anterior acrosome in mouse sperm, as shown by protein localization studies; the heterospecific t-complex allele of Tsga2 carries numerous nonsynonymous mutations in conserved residues and shows reduced testis expression, associating Tsga2 with the 'curlicue' flagellar waveform abnormality in t/t male mice. Sperm protein extraction, protein localization studies, genetic mapping in heterospecific t-complex mice Biology of reproduction Medium 16354795
2022 SPEF2 interacts with RSPH9 (a radial spoke component closely related to RSPH1) in vitro; proteomic analysis of SPEF2-mutant patient sperm showed reduced RSPH1 expression, placing RSPH1 downstream of SPEF2 in sperm flagellar assembly. Proteomic analysis of patient sperm, Western blot, in vitro interaction assay Asian journal of andrology Low 34755699

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. American journal of respiratory and critical care medicine 193 24568568
2013 Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. American journal of human genetics 132 23993197
2015 Immunofluorescence Analysis and Diagnosis of Primary Ciliary Dyskinesia with Radial Spoke Defects. American journal of respiratory cell and molecular biology 104 25789548
2014 Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. Human molecular genetics 76 24518672
2015 RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes. American journal of human genetics 72 26073779
2021 CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis. Human molecular genetics 36 34231842
2015 Mutation analysis in patients with total sperm immotility. Journal of assisted reproduction and genetics 33 25877373
2019 Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. Journal of medical genetics 29 31772028
2021 Bi-allelic truncating variants in CFAP206 cause male infertility in human and mouse. Human genetics 26 34255152
2016 Array-CGH diagnosis in ovarian failure: identification of new molecular actors for ovarian physiology. Journal of ovarian research 26 27716277
2023 Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility. Frontiers in genetics 24 36873931
2007 Radial spoke protein 44 (human meichroacidin) is an axonemal alloantigen of sperm and cilia. Gene 21 17451891
1997 Mapping of eight testis-specific genes to mouse chromosomes. Genomics 19 9403069
2022 Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans. Asian journal of andrology 18 34755699
2021 Structural insights into the cause of human RSPH4A primary ciliary dyskinesia. Molecular biology of the cell 16 33852348
2023 CCDC189 affects sperm flagellum formation by interacting with CABCOCO1. National science review 15 37601242
2016 Novel roles for the radial spoke head protein 9 in neural and neurosensory cilia. Scientific reports 15 27687975
2014 Cognition and hippocampal plasticity in the mouse is altered by monosomy of a genomic region implicated in Down syndrome. Genetics 15 24752061
2021 Different combinations of high-frequency rTMS and cognitive training improve the cognitive function of cerebral ischemic rats. Brain research bulletin 13 34280480
2007 The molecular basis of "curlicue": a sperm motility abnormality linked to the sterility of t haplotype homozygous male mice. Society of Reproduction and Fertility supplement 11 17566267
2011 Identification of testis 14-3-3 binding proteins by tandem affinity purification. Spermatogenesis 10 22332119
2017 Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function. Respiratory research 9 28793908
2005 The mouse T complex gene Tsga2, encoding polypeptides located in the sperm tail and anterior acrosome, maps to a locus associated with sperm motility and sperm-egg interaction abnormalities. Biology of reproduction 8 16354795
2019 An Integrated Analysis of Radial Spoke Head and Outer Dynein Arm Protein Defects and Ciliogenesis Abnormality in Nasal Polyps. Frontiers in genetics 7 31798623
2015 Application of serex-analysis for identification of human colon cancer antigens. Experimental oncology 5 26422100
2014 Disruption of murine Tcte3-3 induces tissue specific apoptosis via co-expression of Anxa5 and Pebp1. Computational biology and chemistry 5 25462330
2021 Whole-exome sequencing reveals a combination of extremely rare single-nucleotide polymorphism of DNAH9 and RSPH1 genes in a Japanese fetus with situs viscerum inversus. Medical molecular morphology 3 34008076
2025 GSTA1 Conferred Tolerance to Osimertinib and Provided Strategies to Overcome Drug-Tolerant Persister in EGFR-Mutant Lung Adenocarcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2 41076079
2025 Clinical, Genetic, Morphological and Functional Correlations in a Large Series of Patients with Primary Ciliary Dyskinesia: A Heterogeneous Disease with a Controversial Diagnosis. Molecular diagnosis & therapy 1 40742517
2023 An Integrated Analysis Reveals Ciliary Abnormalities in Antrochoanal Polyps. Journal of inflammation research 1 36820148
2022 Ciliary and immune dysfunctions and their genetic background in patients with non-cystic fibrosis bronchiectasis in Central Iran. Irish journal of medical science 1 35389161
2022 Subtyping children with asthma by clustering analysis of mRNA expression data. Frontiers in genetics 1 36159986
2026 Disorders of sex development associated with MPI and RSPH1 variants expand the phenotypic spectrum of CDG and PCD in Morocco. Molecular biology reports 0 41533173
2026 Mucociliary and cough clearance in primary ciliary dyskinesia as affected by mutations in RSPH1 or DNAH5. ERJ open research 0 41561107
2026 Multi-time points RNA-seq screening identifies key transcription factors and splicing factors responsive to intermittent hypoxia in the mouse hippocampus. Free radical biology & medicine 0 41672112
2025 Genetic investigation of sinopulmonary diseases in Vietnam: seeking specific causes from non-specific symptoms. Orphanet journal of rare diseases 0 41094464