Affinage

HYDIN

Hydrocephalus-inducing protein homolog · UniProt Q4G0P3

Length
5121 aa
Mass
575.9 kDa
Annotated
2026-06-10
24 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HYDIN is a large axonemal protein of the central pair (CP) apparatus that is required for the proper waveform and beat regulation of motile cilia and flagella (PMID:17296796, PMID:18250199). It localizes specifically to the C2 microtubule of the CP, where it forms the C2b projection (PMID:17296796, PMID:23022101), and functions as a chain-like ASH-domain-containing structural element that connects the C1 and C2 central microtubules, a bridge that also depends on CFAP47 [PMID:bio_10.1101_2024.08.06.606614]. Within the CP-radial spoke control pathway that governs dynein arm activity, HYDIN associates biochemically with the CP proteins CPC1 and the kinesin-like protein KLP1 (PMID:17296796), and its presence is required for recruitment of SPEF2 to the central apparatus in both respiratory cilia and sperm flagella (PMID:31545650, PMID:36873931). HYDIN is also needed to establish and maintain the position of the central pair along the axoneme (PMID:17683645). Loss of HYDIN disrupts ciliary bending, beat frequency, and switch-point transitions between effective and recovery strokes while leaving outer dynein arms, radial spokes, and nodal cilia function intact (PMID:17296796, PMID:18250199, PMID:23022101). In humans, biallelic loss-of-function HYDIN mutations cause primary ciliary dyskinesia with loss of the C2b projection and reduced ciliary beating, and HYDIN deficiency underlies lethal communicating hydrocephalus and male infertility through immotile, structurally abnormal sperm flagella (PMID:18250199, PMID:12719380, PMID:23022101, PMID:30089752, PMID:36873931).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2003 Medium

    Established HYDIN as a hydrocephalus-causing gene and defined where it is expressed, framing it as a ciliated-cell protein before its molecular role was known.

    Evidence cDNA cloning, expression analysis, and identification of the hy3 frameshift mutation in mice

    PMID:12719380

    Open questions at the time
    • Subcellular localization within the axoneme not determined
    • Caldesmon-homology domain is sequence inference only, no functional test
  2. 2007 High

    Placed HYDIN structurally and biochemically within the central pair apparatus, showing it builds the C2b projection and acts in the CP-radial spoke pathway that controls dynein-driven beating.

    Evidence Antibody localization, RNAi knockdown, co-purification with CPC1 and KLP1, and EM in Chlamydomonas

    PMID:17296796

    Open questions at the time
    • Direct vs. indirect nature of CPC1/KLP1 interactions not dissected
    • Mechanism linking C2b loss to switch-point arrest not resolved
  3. 2007 Medium

    Demonstrated that HYDIN is needed to position and maintain the central pair along the full axoneme length, not merely to build a single projection.

    Evidence RNAi, EM, and motility assays in Trypanosoma brucei

    PMID:17683645

    Open questions at the time
    • Molecular basis of CP mispositioning at the basal plate unknown
    • Single organism, single lab
  4. 2008 High

    Confirmed in a mammalian system that HYDIN loss removes a specific CP projection and impairs cilia-driven fluid flow, mechanistically connecting the structural defect to hydrocephalus.

    Evidence EM ultrastructure, high-speed videomicroscopy, and fluid flow analysis in Hydin mutant mice

    PMID:18250199

    Open questions at the time
    • Does not address how the projection regulates dynein activity
    • Sperm and reproductive phenotypes not examined
  5. 2012 High

    Established HYDIN as a human PCD gene and confirmed the C2b projection defect by tomography, while showing nodal cilia and left-right asymmetry are spared.

    Evidence Homozygosity mapping, exome sequencing, EM tomography, and videomicroscopy of cilia and sperm in PCD families

    PMID:23022101

    Open questions at the time
    • Why nodal cilia are unaffected not mechanistically explained
    • Interacting partners maintaining the C2b projection not identified
  6. 2018 Medium

    Provided direct genetic evidence that HYDIN is required for sperm flagellar assembly and motility, extending its role beyond respiratory and ependymal cilia.

    Evidence CRISPR disruption in ESCs, chimeric mice, sperm morphology/motility assays, and ICSI rescue

    PMID:30089752

    Open questions at the time
    • Molecular cause of short-tail phenotype not defined
    • Chimeric, not full knockout, animals
  7. 2020 Medium

    Identified SPEF2 as a HYDIN-dependent CP component, revealing a recruitment relationship usable for PCD diagnosis.

    Evidence Immunofluorescence of SPEF2 in HYDIN-mutant patient respiratory cells

    PMID:31545650

    Open questions at the time
    • Direct physical HYDIN-SPEF2 interaction not demonstrated
    • Whether SPEF2 loss contributes to motility defect not separated from C2b loss
  8. 2023 Medium

    Showed the HYDIN-SPEF2 dependence operates in sperm and that HYDIN loss broadly destabilizes acrosomal, centrosomal, and axonemal components in MMAF patients.

    Evidence Exome sequencing, immunofluorescence, western blot, TEM, and videomicroscopy of patient sperm

    PMID:36742411 PMID:36873931

    Open questions at the time
    • Acrosome/neck disassembly is novel and based on single patient (idx 8)
    • Whether HYDIN acts directly on acrosome/neck or indirectly via flagellar collapse unresolved
  9. 2020 Low

    Proposed a non-canonical role for HYDIN in cardiomyocyte differentiation via GATA4 regulation, distinct from its axonemal function.

    Evidence Knockdown/overexpression in hESC cardiac differentiation, transgenic mice, and GATA4 rescue

    PMID:32376282

    Open questions at the time
    • Mechanistic link between ciliary HYDIN and GATA4 transcription unclear and not replicated
    • Inconsistent with HYDIN's established axonemal localization
  10. 2024 Medium

    Resolved HYDIN's molecular architecture in situ, assigning it as the chain-like ASH-domain protein forming the C1-C2 bridge together with CFAP47.

    Evidence In situ cryo-electron tomography with AlphaFold2-aided modeling and Cfap47 knockout mouse analysis (preprint)

    PMID:bio_10.1101_2024.08.06.606614

    Open questions at the time
    • Preprint, single lab, not independently replicated
    • Atomic model partly inference from AlphaFold2

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the HYDIN-built C1-C2 bridge and C2b projection mechanically transduce signals to regulate dynein activity and beat switch-points remains unresolved.
  • No reconstituted assay of HYDIN-dependent dynein regulation
  • Direct interaction map among HYDIN, CFAP47, SPEF2, CPC1, KLP1 incomplete

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 3
Partners
CFAP47CPC1KLP1SPEF2
Complex memberships
C1-C2 central pair bridgecentral pair apparatus

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 located specifically on the C2 microtubule of the CP apparatus. An ~80% knockdown results in loss of the C2b projection and flagellar arrest at switch points between effective and recovery strokes. HYDIN interacts biochemically with CP proteins CPC1 and kinesin-like protein 1 (KLP1), placing it in the CP-radial spoke control pathway that regulates dynein arm activity. Antibody localization to C2 microtubule; RNAi knockdown; biochemical interaction analyses (co-purification with CPC1 and KLP1); electron microscopy of axoneme ultrastructure The Journal of cell biology High 17296796
2008 In mice, Hydin mutations cause loss of a specific projection on one of the two central pair microtubules of the ciliary axoneme; outer dynein arms and radial spokes are normal. This structural defect impairs ciliary bending and beat frequency in both brain ependymal cilia and tracheal cilia, abolishing fluid flow and causing hydrocephalus. Electron microscopy of axoneme ultrastructure; high-speed videomicroscopy of ciliary beat; comparison of wild-type vs. Hydin mutant mice The Journal of cell biology High 18250199
2003 Hydin encodes a large ~5099 amino acid protein whose loss-of-function (frameshift deletion in exon 15 causing premature termination) causes lethal communicating hydrocephalus. Expression is restricted to ciliated ependymal cells lining brain ventricles, bronchial epithelium, oviduct, and developing spermatocytes. The protein contains a domain homologous to caldesmon, an actin-binding protein. cDNA selection and sequencing; Northern blot analysis; in situ hybridization/expression analysis in neonatal brain; identification of hy3 frameshift mutation Human molecular genetics Medium 12719380
2007 In Trypanosoma brucei, RNAi knockdown of HYDIN causes loss of cell motility accompanied by two sequential central pair microtubule defects: early mispositioning of the central pair and later complete loss of the central pair, both originating at the basal plate. This demonstrates HYDIN's role in positioning and maintaining the central pair along the entire axoneme length. RNAi in Trypanosoma brucei; electron microscopy of flagellar ultrastructure; cell motility assays BMC biology Medium 17683645
2012 Human HYDIN mutations (splice-site and nonsense) cause primary ciliary dyskinesia characterized by loss of the C2b projection of the central pair apparatus in respiratory cilia (demonstrated by electron microscopy tomography), markedly reduced ciliary beating amplitude, and stiff sperm flagella, without affecting nodal cilia function or left-right body asymmetry. Homozygosity mapping; whole-exome sequencing; electron microscopy tomography of respiratory cilia; high-speed videomicroscopy of cilia and sperm American journal of human genetics High 23022101
2020 SPEF2 protein is absent from HYDIN-mutant respiratory cilia as detected by immunofluorescence microscopy, revealing that SPEF2 localization to the central pair apparatus is dependent on functional HYDIN. This dependence is used diagnostically to detect HYDIN-related PCD. Immunofluorescence microscopy of respiratory cells from HYDIN-mutant individuals; genetic analysis confirming HYDIN mutations American journal of respiratory cell and molecular biology Medium 31545650
2018 HYDIN is essential for spermiogenesis in mice: chimeric mice with Hydin-disrupted spermatogonial stem cells produce spermatozoa with short tails that are completely immotile, establishing a direct requirement for HYDIN in sperm flagella assembly and motility. CRISPR/Cas9 disruption of Hydin in ESCs; chimeric mouse generation; morphological analysis of sperm tail length; motility assays; ICSI rescue experiment Experimental animals Medium 30089752
2023 In HYDIN-deficient infertile men, immunofluorescence shows reduction of SPEF2 in sperm flagella, revealing a HYDIN–SPEF2 interaction in sperm analogous to that in respiratory cilia. Additionally, loss of HYDIN causes reduction of multiple flagellar components including acrosome markers (ACTL7A, ACROSIN, PLCζ1), centrosome marker (Centrin1), and axonemal proteins (TOMM20, SEPT4, SPAG6, RSPHs), and results in multiple morphological abnormalities of the sperm flagella (MMAF). Whole-exome sequencing; immunofluorescence microscopy of sperm; western blot; transmission electron microscopy; high-speed video microscopy Frontiers in genetics Medium 36873931
2023 HYDIN-deficient patient sperm show loss of HYDIN protein along with disassembly of acrosome components and the neck/centrosome region in addition to flagellar structural defects, providing first evidence that HYDIN function extends to acrosome and neck integrity in sperm. Whole-exome sequencing identifying compound heterozygous HYDIN splice variants; western blot and immunostaining for HYDIN, acrosome markers, centrosome markers, and flagellar components in patient sperm; SEM and TEM Frontiers in endocrinology Low 36742411
2020 HYDIN loss-of-function in human embryonic stem cells reduces GATA4 expression and impairs cardiomyocyte differentiation; shRNA-mediated 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 hESCs, and GATA4 overexpression rescues the differentiation defect caused by HYDIN knockdown. siRNA/shRNA knockdown and overexpression in hESC cardiac differentiation; transgenic Hydin knockdown mice; GATA4 rescue construct; characterization of cardiac-specific phenotype Mechanisms of development Low 32376282
2024 In situ cryo-electron tomography of intact mouse sperm axoneme at sub-nanometer resolution reveals that HYDIN is a long chain-like ASH-domain-containing protein responsible for connecting the C1 and C2 central pair microtubules. Cfap47 knockout mice show a hollowing of the C1-C2 bridge structure, demonstrating HYDIN's structural role in the bridge connecting the two central microtubules. In situ cryo-electron tomography; AlphaFold2-aided atomic model building; Cfap47 knockout mouse with structural and motility phenotype analysis bioRxiv (preprint)preprint Medium bio_10.1101_2024.08.06.606614

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 231 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 58 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 47 24700285
2006 A 360-kb interchromosomal duplication of the human HYDIN locus. Genomics 41 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 25 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 15 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 11 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.) 5 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
2023 HYDIN mutation status as a potential predictor of immune checkpoint inhibitor efficacy in melanoma. Aging 1 37595251
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

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