Affinage

HYDIN

Hydrocephalus-inducing protein homolog · UniProt Q4G0P3

Length
5121 aa
Mass
575.9 kDa
Annotated
2026-04-28
24 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HYDIN encodes a large axonemal protein that is a structural component of the central pair (CP) apparatus in motile 9+2 cilia and sperm flagella, where it localizes specifically to the C2b projection and forms a chain-like bridge connecting the C1 and C2 central microtubules (PMID:17296796, PMID:18250199, PMID:23022101). Loss of HYDIN eliminates the C2b projection, disrupts ciliary beat waveform and flagellar motility, abolishes SPEF2 recruitment to the CP, and impairs the CP–radial spoke signaling pathway that regulates dynein arm activity (PMID:17296796, PMID:31545650, PMID:30089752). In Chlamydomonas, HYDIN physically interacts with CP proteins CPC1 and KLP1 (PMID:17296796). Homozygous loss-of-function mutations in human HYDIN cause primary ciliary dyskinesia characterized by reduced respiratory ciliary beating and male infertility without situs inversus, and in mice Hydin mutations produce lethal hydrocephalus (PMID:23022101, PMID:12719380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 High

    Identification of Hydin as the gene mutated in hy3 hydrocephalic mice established that this large, previously uncharacterized gene is expressed in ciliated epithelia and spermatocytes and is essential for brain ventricular function.

    Evidence Positional cloning and cDNA selection in hy3 mutant mice; Northern and in situ hybridization for expression

    PMID:12719380

    Open questions at the time
    • No ultrastructural basis for the hydrocephalus phenotype was determined
    • Protein localization within the cilium was unknown
    • Whether Hydin functions in ciliary motility per se or in ciliogenesis was unclear
  2. 2007 High

    Localization of Hydin to the C2 microtubule of the central pair and demonstration that its depletion removes the C2b projection and arrests flagellar beating at stroke transition points established HYDIN as a CP structural protein that regulates dynein-driven motility via the CP–radial spoke pathway.

    Evidence Antibody immunodecoration of isolated Chlamydomonas axonemes, RNAi knockdown, co-IP with CPC1 and KLP1, electron microscopy

    PMID:17296796

    Open questions at the time
    • Whether the same C2b-specific role applies in vertebrate cilia was untested
    • The precise molecular contacts between HYDIN and other CP proteins were unresolved
    • Trypanosoma RNAi showed a more severe complete CP loss phenotype, leaving species-specific functions uncertain
  3. 2008 High

    Extending the Chlamydomonas findings to mammals, analysis of Hydin-mutant mouse cilia showed that HYDIN is required for normal ciliary beat frequency and fluid flow, with loss of a specific central microtubule projection but intact dynein arms and radial spokes, confirming a conserved structural role.

    Evidence Electron microscopy and high-speed videomicroscopy of brain ependymal and tracheal cilia from Hydin-mutant mice

    PMID:18250199

    Open questions at the time
    • Human disease relevance had not yet been demonstrated
    • Which central microtubule projection was lost (C2b vs. other) could not be unambiguously assigned in mouse EM
  4. 2012 High

    Discovery that homozygous HYDIN mutations cause human primary ciliary dyskinesia without laterality defects, combined with electron tomography confirming C2b projection loss, established HYDIN as a PCD disease gene and demonstrated that the CP apparatus is dispensable for left-right axis determination.

    Evidence Homozygosity mapping and whole-exome sequencing in consanguineous families; electron tomography of patient respiratory cilia; high-speed videomicroscopy

    PMID:23022101

    Open questions at the time
    • Male infertility phenotype in human HYDIN mutation carriers was not yet characterized
    • Downstream molecular consequences of C2b loss on other CP components were unknown
  5. 2018 Medium

    CRISPR disruption of Hydin in mice demonstrated that HYDIN is essential for spermiogenesis, with mutant spermatozoa showing short immotile tails, extending HYDIN's functional requirement to mammalian sperm flagella.

    Evidence CRISPR/Cas9 disruption in mouse ES cells, chimeric mice, fluorescent sperm motility analysis, ICSI rescue

    PMID:30089752

    Open questions at the time
    • Whether the flagellar defect reflects CP-specific loss or broader structural disassembly was not determined
    • Ultrastructural analysis of the sperm central pair was not performed
  6. 2020 Medium

    Demonstration that SPEF2 fails to localize to cilia and sperm flagella in HYDIN-mutant individuals revealed a co-dependent relationship between these two CP proteins, defining HYDIN as required for SPEF2 recruitment to the central apparatus.

    Evidence Immunofluorescence of respiratory cilia and sperm from genetically confirmed HYDIN-mutant patients

    PMID:31545650

    Open questions at the time
    • Whether HYDIN and SPEF2 interact directly or co-depend through a shared structural scaffold was not resolved
    • No biochemical interaction assay between HYDIN and SPEF2 was performed
  7. 2024 Medium

    Sub-nanometer cryo-electron tomography of mouse sperm axonemes resolved HYDIN as a chain-like ASH-domain protein forming the C1–C2 bridge of the central apparatus, providing the first near-atomic structural model of HYDIN within the intact axoneme.

    Evidence In situ cryo-ET of mouse sperm with AlphaFold2-assisted atomic model building (preprint)

    PMID:bio_10.1101_2024.08.06.606614

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Structural model has not been validated by mutagenesis of predicted contact sites
    • How the C1–C2 bridge mediates signal transduction to dynein arms is structurally unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise mechanism by which HYDIN transmits regulatory signals from the central pair to dynein arms via radial spokes, and the structural basis of its interactions with CPC1, KLP1, and SPEF2, remain unresolved at atomic resolution.
  • No high-resolution structure of HYDIN in complex with CPC1 or KLP1 exists
  • The caldesmon-homology domain's function within the axoneme is uncharacterized
  • Whether HYDIN has non-ciliary functions (e.g., in cardiogenesis) requires independent replication

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4
Partners
CPC1KLP1SPAG6SPEF2
Complex memberships
Central pair apparatus (C2b projection / C1-C2 bridge)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Chlamydomonas reinhardtii hydin is a central pair (CP) protein localized specifically to the C2 microtubule of the CP apparatus; 80% knockdown results in loss of the C2b projection and flagellar arrest at switch points between effective and recovery strokes; biochemical analyses revealed hydin interacts with CP proteins CPC1 and kinesin-like protein 1 (KLP1), placing hydin in the CP-radial spoke control pathway that regulates dynein arm activity. Antibody localization (immunodecoration of C2 microtubule), RNAi knockdown, co-immunoprecipitation/biochemical interaction assays, electron microscopy The Journal of cell biology High 17296796
2008 Mouse Hydin is required for normal ciliary motility; Hydin-mutant cilia have a normal 9+2 axoneme with normal dynein arms and radial spokes but lack a specific projection on one of the two central microtubules, resulting in reduced ciliary beat frequency, tendency to stall, inability to generate fluid flow, and consequent hydrocephalus. Electron microscopy ultrastructural analysis, high-speed videomicroscopy, ciliary beat frequency measurement, morphological comparison of wild-type vs. mutant mouse cilia The Journal of cell biology High 18250199
2007 In Trypanosoma brucei, RNAi-mediated loss of Hydin causes misposition of the central pair microtubules at early time points and complete loss of the central pair at later time points, with both defects originating at the basal plate, demonstrating Hydin's role in positioning and maintaining central pair microtubules throughout the axoneme length. RNAi in Trypanosoma brucei, electron microscopy of flagellar ultrastructure, motility assays BMC biology Medium 17683645
2003 Mouse Hydin is expressed in ciliated ependymal cells lining brain ventricles, ciliated bronchial and oviductal epithelium, and developing spermatocytes; a single CG deletion in exon 15 in hy3 mutants creates a premature stop codon eliminating 89% of the protein, causing lethal hydrocephalus. The Hydin protein contains a domain homologous to caldesmon, an actin-binding protein, suggesting a cytoskeletal interaction. Positional cloning, cDNA selection, Northern analysis, sequencing of hy3 mutant allele, in situ expression analysis Human molecular genetics High 12719380
2012 Homozygous loss-of-function mutations in human HYDIN cause primary ciliary dyskinesia with markedly reduced respiratory cilia beating amplitude and stiff sperm flagella, but without left-right body asymmetry randomization; electron microscopy tomography of HYDIN-mutant respiratory cilia demonstrates absence of the C2b projection of the central pair apparatus, consistent with HYDIN being the structural component responsible for this projection. Homozygosity mapping, whole-exome sequencing, electron microscopy tomography of respiratory cilia, high-speed videomicroscopy American journal of human genetics High 23022101
2020 The CP-associated protein SPEF2 is absent from cilia of HYDIN-mutant cells, revealing that SPEF2 localization to the central pair apparatus depends on functional HYDIN; this interaction is also observed in sperm flagella where HYDIN and SPEF2 show co-dependent localization. Immunofluorescence microscopy of respiratory cilia and sperm from HYDIN-mutant individuals, genetic confirmation by next-generation sequencing American journal of respiratory cell and molecular biology Medium 31545650
2018 HYDIN is essential for spermiogenesis in mice; Hydin-disrupted spermatozoa have short tails and are completely immotile, demonstrating a direct structural role of HYDIN in sperm flagella assembly and motility. CRISPR/Cas9 disruption of Hydin in ES cells, chimeric mouse generation, fluorescent sperm motility analysis, ICSI rescue experiment Experimental animals Medium 30089752
2020 HYDIN functions as a positive regulator of cardiomyocyte differentiation in human embryonic stem cells by promoting GATA4 expression; cardiac-specific Hydin knockdown in mice leads to Gata4 downregulation and increased atrial septal defect risk; a human HYDIN variant (c.A2207C) reduces GATA4 expression in differentiating hESC cells. siRNA knockdown, overexpression, shRNA-GATA4 cDNA rescue in hESC cardiac differentiation; shRNA transgenic mice; cardiac-specific knockdown with ASD phenotyping Mechanisms of development Low 32376282
2023 Loss of HYDIN function in sperm causes absence or severe reduction of flagellar components including SPEF2, SPAG6, RSPHs, TOMM20, SEPT4, and acrosome/centrosome markers (ACTL7A, ACROSIN, PLCζ1, Centrin1), indicating HYDIN is required for the structural integrity of multiple flagellar compartments beyond the central pair. Whole-exome sequencing, western blot, immunostaining of sperm from HYDIN compound heterozygous patients, transmission electron microscopy Frontiers in endocrinology Low 36742411
2024 In situ cryo-electron tomography of mouse sperm axoneme at sub-nanometer resolution identified HYDIN as a long chain-like ASH-domain-containing protein responsible for connecting central pair microtubules C1 and C2; atomic model built with AlphaFold2 assigns HYDIN to the C1-C2 bridge in the central apparatus. In situ cryo-electron tomography, near-complete atomic model building with AlphaFold2, Cfap47 knockout mouse validation bioRxivpreprint Medium bio_10.1101_2024.08.06.606614
2023 Pathogenic HYDIN variants in sperm cause absence of SPEF2 in sperm flagella, and pathogenic CCDC39 variants cause absence of CCDC39 and SPEF2, revealing a co-dependent interaction between HYDIN and SPEF2 in sperm flagella analogous to what is seen in respiratory cilia. Immunofluorescence microscopy on sperm from genetically confirmed HYDIN-mutant individuals, next-generation sequencing, transmission electron microscopy Frontiers in genetics Medium 36873931

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry. American journal of human genetics 229 23022101
2008 Mutations in Hydin impair ciliary motility in mice. The Journal of cell biology 207 18250199
2003 Congenital hydrocephalus in hy3 mice is caused by a frameshift mutation in Hydin, a large novel gene. Human molecular genetics 129 12719380
2007 Chlamydomonas reinhardtii hydin is a central pair protein required for flagellar motility. The Journal of cell biology 119 17296796
2007 The hydrocephalus inducing gene product, Hydin, positions axonemal central pair microtubules. BMC biology 62 17683645
2020 SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics. American journal of respiratory cell and molecular biology 57 31545650
2014 Precise genetic mapping and integrative bioinformatics in Diversity Outbred mice reveals Hydin as a novel pain gene. Mammalian genome : official journal of the International Mammalian Genome Society 46 24700285
2006 A 360-kb interchromosomal duplication of the human HYDIN locus. Genomics 40 16938426
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
2018 Chimeric analysis with newly established EGFP/DsRed2-tagged ES cells identify HYDIN as essential for spermiogenesis in mice. Experimental animals 16 30089752
2013 Alternative variants of human HYDIN are novel cancer-associated antigens recognized by adaptive immunity. Cancer immunology research 14 24777681
2007 Hydin seek: finding a function in ciliary motility. The Journal of cell biology 12 17296793
2024 Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia. European journal of human genetics : EJHG 10 38605126
2018 1q21.1 microduplication: large verbal-nonverbal performance discrepancy and ddPCR assays of HYDIN/HYDIN2 copy number. NPJ genomic medicine 10 30155272
2024 Heterozygous cis HYDIN mutations cause primary ciliary dyskinesia. Med (New York, N.Y.) 4 39317196
2023 Novel HYDIN variants associated with male infertility in two Chinese families. Frontiers in endocrinology 4 36742411
2020 HYDIN loss-of-function inhibits GATA4 expression and enhances atrial septal defect risk. Mechanisms of development 4 32376282
2025 Robust detection of pathogenic HYDIN variants that cause primary ciliary dyskinesia using RNA-seq of nasal mucosa. Journal of medical genetics 3 39805680
2017 [Primary ciliary dyskinesia with HYDIN gene mutations in a child and literature review]. Zhonghua er ke za zhi = Chinese journal of pediatrics 3 28441829
2024 HYDIN variants cause primary ciliary dyskinesia in the Finnish population. Pediatric pulmonology 1 39291810
2024 Hydin as the Candidate Master Sex Determination Gene in Channel Catfish (Ictalurus punctatus) and Its Epigenetic Regulation. Marine biotechnology (New York, N.Y.) 1 39579181
2025 The relationship between HYDIN and fallopian tubal cilia loss in patients with epithelial ovarian cancer. Frontiers in oncology 0 39850822
2025 Towards a practical tool to identify HYDIN genotype using high-speed videomicroscopy. Thorax 0 41073067
2023 HYDIN mutation status as a potential predictor of immune checkpoint inhibitor efficacy in melanoma. Aging 0 37595251