Affinage

RSPH1

Radial spoke head 1 homolog · UniProt Q8WYR4

Length
309 aa
Mass
35.1 kDa
Annotated
2026-06-10
36 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RSPH1 is a radial spoke head protein of the motile cilium and sperm flagellum axoneme, required for assembly of the radial spoke (RS) head complex that tethers the central pair of microtubules and shapes ciliary waveform (PMID:23993197, PMID:24518672, PMID:33852348). It localizes within the radial spokes of sperm flagella and of tracheal and ependymal cilia (PMID:17451891), and biallelic loss-of-function mutations abolish detectable axonemal RSPH1 and cause primary ciliary dyskinesia with central-complex and radial-spoke defects (PMID:23993197). RSPH1 occupies a defined position in a hierarchical RS-head assembly pathway: RSPH4A acts as the core scaffold whose loss prevents axonemal assembly of both RSPH1 and RSPH9, whereas loss of RSPH1 causes co-loss of RSPH9 (but not RSPH4A), and RSPH9 loss affects only RSPH9 (PMID:25789548). Cryo-electron tomography localizes RSPH1's specific contribution to the heads of RS1 and RS2 (PMID:33852348). Functionally, RSPH1 deficiency produces a distinctive phenotype of near-normal ciliary beat frequency with an abnormal circular beat pattern, elevated nasal nitric oxide, and relatively mild lung disease, indicating residual axonemal function (PMID:24568568); structurally it underlies transposition of peripheral microtubules into the central-pair space with intermittent central-pair loss (PMID:24518672). RSPH1 mutations also cause male infertility through sperm dysmotility and altered flagellar RSPH1 composition (PMID:36873931), and in the flagellum RSPH1 participates in radial-spoke and central-pair networks involving CFAP65, CCDC189, and DNAH12 (PMID:34231842, PMID:37601242).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2007 Medium

    Established where the RSPH1 protein resides, placing it physically within axonemal radial spokes of both flagella and cilia before any disease link was known.

    Evidence EM immunocytochemistry, immunofluorescence and expression analysis in testis and ciliated tissues

    PMID:17451891

    Open questions at the time
    • No functional consequence of localization tested
    • Significance of the 38 vs 44 kDa sperm processing unresolved
  2. 2013 High

    Linked RSPH1 to human disease, showing loss-of-function mutations abolish axonemal RSPH1 and cause PCD with central-complex and radial-spoke defects, establishing RSPH1 as required for RS/CC assembly.

    Evidence Homozygosity mapping, whole-exome sequencing and immunofluorescence of airway cilia across 10 families

    PMID:23993197

    Open questions at the time
    • Did not resolve which other RS subunits depend on RSPH1
    • Mechanism of central-complex defect not structurally defined
  3. 2014 High

    Defined the structural and functional consequence of RSPH1 loss: co-loss of RSPH4A and RSPH9 with microtubule transposition, plus a distinctive circular waveform with preserved beat frequency, indicating partial axonemal function.

    Evidence High-resolution immunofluorescence, TEM, high-speed video microscopy, nasal NO and lung function in biallelic patients

    PMID:24518672 PMID:24568568

    Open questions at the time
    • Basis of residual ciliary function not explained
    • RS3 contribution not assessed
  4. 2015 High

    Resolved the RS-head assembly hierarchy, ordering RSPH4A as scaffold upstream of RSPH1, which is in turn upstream of RSPH9, and placed RSPH3 at the RS stalk/neck independent of RSPH1.

    Evidence Systematic immunofluorescence across RSPH9/RSPH4A/RSPH1 and RSPH3-mutant patient cilia

    PMID:25789548 PMID:26073779

    Open questions at the time
    • Direct biochemical interactions among RS-head proteins not shown
    • No reconstitution of assembly order in vitro
  5. 2021 High

    Provided sub-axonemal structural resolution by cryo-ET, mapping RSPH1's contribution specifically to the heads of RS1 and RS2 and distinguishing it from RSPH4A's broader arch-domain role.

    Evidence Cryo-electron tomography and subtomogram averaging of patient-derived RSPH1-/- and RSPH4A-/- cilia

    PMID:33852348

    Open questions at the time
    • Atomic-resolution placement of RSPH1 within the head not determined
    • Functional link between RS1/RS2 head loss and waveform defect not mechanistically dissected
  6. 2021 Medium

    Extended RSPH1 biology to spermiogenesis, identifying cytoplasmic and flagellar networks (CFAP65, CFAP206) acting upstream of or alongside RSPH1 in sperm radial spoke assembly.

    Evidence Endogenous co-IP, immunostaining and KO mouse models for CFAP65 and CFAP206

    PMID:34231842 PMID:34255152

    Open questions at the time
    • Direct RSPH1 binding to CFAP206 not shown
    • Whether these interactions are flagellum-specific unresolved
  7. 2023 Medium

    Demonstrated that RSPH1 mutations cause male infertility through sperm dysmotility with absent or reduced flagellar RSPH1, extending the disease phenotype to reproduction.

    Evidence NGS, immunofluorescence and TEM of sperm flagella, high-speed video microscopy in patients

    PMID:36873931

    Open questions at the time
    • Cohort from single lab
    • Quantitative relationship between RSPH1 loss and motility not established
  8. 2024 Medium

    Implicated RSPH1 in central-pair stability in sperm via interaction with DNAH12, RSPH9 and DNAJB13, linking the RS head to central-pair integrity selectively in flagella.

    Evidence Co-IP and Dnah12 KO/knock-in mouse models with TEM and immunofluorescence (preprint)

    PMID:bio_10.1101_2024.06.20.599934

    Open questions at the time
    • Preprint, single lab
    • Why central-pair loss occurs in sperm but not cilia unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RSPH1-bearing RS heads of RS1/RS2 mechanically constrain the central pair to produce normal versus circular ciliary waveform, and what distinguishes the flagellar from the ciliary requirement.
  • No atomic-resolution RS-head model with RSPH1 placed
  • Mechanism converting head loss to waveform change unknown
  • Tissue-specific differences in central-pair dependence unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1474165 Reproduction 1
Partners
CCDC189CFAP65DNAH12DNAJB13RSPH4ARSPH9
Complex memberships
axonemal radial spoke head (RS1/RS2)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 RSPH1 (RSP44/human meichroacidin) protein localizes within the radial spokes of the axonemal complex of sperm flagella and in cilia of tracheal and ependymal epithelial cells, as demonstrated by EM immunocytochemistry and immunofluorescence; it is expressed in testis and ciliated tissues and may undergo proteolytic processing in sperm (38 kDa isoform vs. 44 kDa form in somatic tissues). EM immunocytochemistry, immunofluorescence, Western blot, Northern blot, RT-PCR Gene Medium 17451891
2013 Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex (CC) and radial-spoke (RS) defects; wild-type RSPH1 localizes within cilia of airway cells but is undetectable in cilia from individuals with RSPH1 loss-of-function mutations, establishing that RSPH1 is required for proper assembly of CCs and RSs in human airway cilia. Homozygosity mapping, whole-exome sequencing, immunofluorescence of airway cilia, high-speed video microscopy, transcript analysis from airway cells American journal of human genetics High 23993197
2014 RSPH1 mutations result in loss of the entire radial spoke head structure from cilia: high-resolution immunofluorescence of RSPH1-mutated cilia revealed co-loss of RSPH4A and RSPH9 along with RSPH1, and ultrastructural analysis showed transposition of peripheral outer microtubules into the empty central pair space with intermittent central pair loss, suggesting RSPH1 is required for tethering central microtubules via radial spoke heads. Targeted NGS panel, high-resolution immunofluorescence microscopy, transmission electron microscopy Human molecular genetics High 24518672
2014 Biallelic loss-of-function mutations in RSPH1 cause PCD with a unique phenotype: cilia show normal beat frequency but an abnormal circular beat pattern, higher nasal nitric oxide levels, and milder lung disease compared to other PCD genotypes, indicating residual ciliary function despite RSPH1 loss. Whole-exome sequencing, Sanger sequencing, high-speed video microscopy of ciliary beat, nasal nitric oxide measurement, lung function testing American journal of respiratory and critical care medicine High 24568568
2015 RSPH4A is the core protein of the radial spoke head: absence of RSPH4A (due to RSPH4A mutations) results in deficient axonemal assembly of both RSPH1 and RSPH9. Conversely, RSPH1 mutations cause loss of RSPH9 from the axoneme but not RSPH4A, while RSPH9 mutations cause loss of RSPH9 alone without affecting RSPH1 or RSPH4A assembly, defining a hierarchical assembly order for the RS head complex. High-resolution immunofluorescence analysis of respiratory cilia in 21 individuals with biallelic mutations in RSPH9, RSPH4A, and RSPH1 American journal of respiratory cell and molecular biology High 25789548
2015 RSPH3 mutations cause loss of RSPH3 from cilia while RSPH23 (RS-neck protein), RSPH1 and RSPH4A (RS-head proteins) remain present within cilia, placing RSPH3 at the RS stalk/neck upstream of the RS head proteins and demonstrating that RSPH1 and RSPH4A can assemble independently of RSPH3. Immunofluorescence of respiratory epithelial cells from RSPH3-mutant individuals American journal of human genetics Medium 26073779
2021 In RSPH4A-/- human respiratory cilia, cryo-electron tomography revealed loss of radial spoke heads of RS1 and RS2 (but not RS3) with additional defects in arch domains adjacent to RS1 and RS2 heads — a pattern similar to but distinct from RSPH1-/- cilia (which lacked RS1 and RS2 heads without arch domain defects), providing structural resolution of RSPH1's specific contribution to the RS head of RS1 and RS2. Cryo-electron tomography (cryo-ET) and subtomogram averaging of patient-derived human respiratory cilia Molecular biology of the cell High 33852348
2021 CFAP65 forms a cytoplasmic protein network with RSPH1 (along with MNS1, TPPP2, ZPBP1 and SPACA1) during spermiogenesis, as demonstrated by endogenous co-immunoprecipitation and immunostaining in mouse testes. Endogenous co-immunoprecipitation, immunostaining, Cfap65 knockout mouse model, proteomics Human molecular genetics Medium 34231842
2021 In CFAP206-mutant patient sperm cells, immunostaining demonstrated absence of both WDR66 and RSPH1 proteins, suggesting CFAP206 is required upstream of RSPH1 for proper radial spoke assembly in sperm flagella. Immunostaining of patient sperm, CRISPR-Cas9 Cfap206 knockout mouse Human genetics Medium 34255152
2023 Pathogenic variants in RSPH1 cause male infertility due to sperm cell dysmotility and abnormal flagellar RSPH1 protein composition; immunofluorescence microscopy of sperm flagella confirmed absence or severe reduction of RSPH1 in RSPH1-mutant individuals, and HYDIN-mutant individuals also showed MMAF, with RSPH1 flagellar composition affected. NGS genetic testing, immunofluorescence microscopy of sperm flagella, transmission electron microscopy, high-speed video microscopy, semen analysis Frontiers in genetics Medium 36873931
2023 CCDC189 interacts with RSPH1 (the radial-spoke-specific protein) as shown by co-immunoprecipitation and mass spectrometry in mouse sperm axonemes; CCDC189 inactivation causes downregulation of RSPH1-associated partner CABCOCO1, placing CCDC189 as a radial-spoke-associated protein upstream of RSPH1 interactions in sperm flagellum formation. Co-immunoprecipitation, mass spectrometry, immunoelectron microscopy, Ccdc189 and Cabcoco1 knockout mice National science review Medium 37601242
2011 TSGA2 (RSPH1) was identified as a novel 14-3-3ζ binding partner 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) of 14-3-3ζ complexes from transgenic mouse testis, LC-MS/MS identification Spermatogenesis Low 22332119
2005 Mouse TSGA2 (ortholog of RSPH1) polypeptides localize in major sperm tail structures and also appear in the vicinity of the anterior acrosome; heterospecific t-complex alleles of Tsga2 carry numerous nonsynonymous mutations in otherwise conserved residues and show highly reduced testis expression, identifying Tsga2 as a candidate for the Ccub1 genetic factor underlying the 'curlicue' sperm motility abnormality. Motility assays, protein localization by immunofluorescence, genetic mapping, expression analysis Biology of reproduction Low 16354795
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 in mouse models; DNAH12 deficiency leads to central pair loss in sperm but not in cilia. Co-immunoprecipitation, Dnah12 knockout and knock-in mouse models, transmission electron microscopy, immunofluorescence bioRxivpreprint Medium bio_10.1101_2024.06.20.599934

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 195 24568568
2013 Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. American journal of human genetics 133 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 34 25877373
2019 Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia. Journal of medical genetics 31 31772028
2021 Bi-allelic truncating variants in CFAP206 cause male infertility in human and mouse. Human genetics 27 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 25 36873931
2007 Radial spoke protein 44 (human meichroacidin) is an axonemal alloantigen of sperm and cilia. Gene 21 17451891
2022 Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans. Asian journal of andrology 19 34755699
1997 Mapping of eight testis-specific genes to mouse chromosomes. Genomics 19 9403069
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
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 3 41076079
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 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 2 40742517
2026 Mucociliary and cough clearance in primary ciliary dyskinesia as affected by mutations in RSPH1 or DNAH5. ERJ open research 1 41561107
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 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

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