Affinage

DYNC2H1

Cytoplasmic dynein 2 heavy chain 1 · UniProt Q8NCM8

Length
4307 aa
Mass
492.6 kDa
Annotated
2026-06-09
42 papers in source corpus 10 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DYNC2H1 encodes the heavy chain of cytoplasmic dynein-2, the motor that drives retrograde intraflagellar transport (IFT) in cilia and flagella (PMID:9971742, PMID:10545497). Studies of the orthologous heavy chains in Chlamydomonas and C. elegans established that loss of this motor abolishes retrograde IFT while leaving anterograde transport intact, causing severely shortened cilia and redistribution of IFT raft components and the anterograde kinesin-II motor and its cargo into the ciliary compartment (PMID:9971742, PMID:10545497). The protein is a cytoplasmic dynein isoform distinct from conventional dynein-1 and from axonemal dyneins, and its expression rises during ciliogenesis (PMID:8832411). By recycling IFT machinery from the ciliary tip, dynein-2 is required for normal cilium assembly and length, and it acts upstream of ciliary Hedgehog signal transduction (PMID:25645819). In humans, biallelic loss-of-function and hypomorphic DYNC2H1 mutations cause skeletal ciliopathies (asphyxiating thoracic dystrophy/short rib-polydactyly syndrome), with patient cells showing shortened cilia, abnormal microtubule architecture, and accumulation of anterograde IFT proteins such as IFT88 at ciliary tips—the diagnostic signature of a retrograde IFT defect (PMID:19361615, PMID:19442771, PMID:23456818); missense mutations cluster in functional domains including the ATP motor domain, and hypomorphic variants directly impair dynein-2 motility in vitro (PMID:23456818, PMID:32753734). A retina-predominant DYNC2H1 transcript exists whose selective disruption causes nonsyndromic inherited retinal degeneration (PMID:32753734). Beyond cilia, DYNC2H1 has been implicated in nuclear localization of the DNA repair proteins XPC and CBX5 in glioblastoma cells (PMID:31347685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Established that the dynein-2 heavy chain is the dedicated retrograde IFT motor, resolving how IFT machinery returns from the ciliary tip while anterograde transport continues independently.

    Evidence Genetic deletion of DHC1b in Chlamydomonas with IFT particle redistribution assay and flagellar biochemical fractionation, plus live-animal IFT imaging of che-3 mutants in C. elegans

    PMID:10545497 PMID:9971742

    Open questions at the time
    • Did not resolve the molecular composition of the dynein-2 holocomplex or its regulatory subunits
    • Mechanism of motor loading/unloading at the ciliary tip not addressed
  2. 1996 Medium

    Defined DHC1b/DYNC2H1 as a distinct cytoplasmic dynein isoform separate from conventional dynein-1 and axonemal dyneins, and linked its expression to ciliogenesis.

    Evidence Isoform-specific antibody immunofluorescence and Western blot in cultured rat tracheal epithelial cells across ciliogenesis

    PMID:8832411

    Open questions at the time
    • Reported cytoplasmic (non-ciliary) localization not reconciled with later retrograde IFT motor role
    • Single-lab antibody-based localization
  3. 2009 High

    Connected DYNC2H1 loss of function to a human skeletal ciliopathy, demonstrating that the motor is essential for cilium generation and maintenance in humans.

    Evidence Homozygosity mapping and Sanger sequencing in multiple families with patient-derived chondrocyte cilia/microtubule morphology analysis

    PMID:19361615 PMID:19442771

    Open questions at the time
    • Did not establish genotype-phenotype correlation across mutation types
    • Mechanism linking ciliary defect to skeletal dysplasia not detailed
  4. 2013 Medium

    Provided the cellular signature of the retrograde defect in patients and mapped mutations to the motor domain, confirming motor activity is the critical function.

    Evidence Exome sequencing, SNP mapping, and patient fibroblast immunofluorescence showing anterograde IFT protein (IFT88) accumulation at ciliary tips

    PMID:23456818

    Open questions at the time
    • No direct biochemical measurement of motor activity for the variants
    • Single-lab cellular readout
  5. 2015 Medium

    Placed DYNC2H1-dependent retrograde IFT upstream of ciliary Hedgehog signaling, linking the transport defect to a developmental signaling pathway.

    Evidence Maternal-zygotic dhc2 mutant medaka with ciliary phenotyping, Ptch1 ciliary immunolocalization, and Hh pathway gene expression

    PMID:25645819

    Open questions at the time
    • Hh defects were partial; quantitative contribution of DYNC2H1 to Hh output unresolved
    • Single model organism, single lab
  6. 2019 Medium

    Implicated DYNC2H1 in a non-ciliary role—nuclear import of DNA repair proteins—underlying chemoresistance in glioblastoma.

    Evidence siRNA knockdown with subcellular proteomics, XPC/CBX5 localization imaging, and TMZ sensitivity assays in MGMT-deficient glioblastoma cells in vitro and in vivo

    PMID:31347685

    Open questions at the time
    • Direct physical interaction of DYNC2H1 with XPC/CBX5 not established
    • Mechanistic basis for a cytoplasmic dynein-2 heavy chain mediating nuclear transport unclear
    • Single lab
  7. 2020 High

    Directly demonstrated that hypomorphic variants impair dynein-2 motility and identified a tissue-specific transcript whose disruption causes isolated retinal disease, expanding the allelic and phenotypic spectrum.

    Evidence In vitro dynein motility reconstitution assay, fibroblast IFT88 cilia assay, iPSC-derived retinal organoids, and genome/exome sequencing

    PMID:32753734

    Open questions at the time
    • Structural basis of motility impairment for specific variants not resolved
    • Regulation of the retina-predominant transcript not characterized
  8. 2025 Low

    Linked DYNC2H1-dependent ciliary function to production of a paracrine wound-healing secretome, extending its role to intercellular signaling.

    Evidence Dync2h1-KO NIH/3T3 cells with conditioned medium transfer, fractionation, untargeted metabolomics, and transcriptomics (preprint)

    PMID:bio_10.1101_2025.08.20.671189

    Open questions at the time
    • Preprint, single lab, not peer reviewed
    • DYNC2H1-specific contribution not isolated from general loss of cilia
    • Indirect readout through conditioned medium

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DYNC2H1 might mediate nuclear transport of DNA repair proteins, mechanistically distinct from its retrograde IFT role, remains unexplained.
  • No structural model of dynein-2 with non-ciliary cargo
  • No reciprocal physical-interaction validation for XPC/CBX5
  • Tissue specificity of the non-ciliary role unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005929 cilium 2 GO:0005829 cytosol 1
Pathway
GO:0005856 cytoskeleton 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1
Partners
IFT88
Complex memberships
cytoplasmic dynein-2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 DHC1b (DYNC2H1 ortholog in Chlamydomonas) is required for retrograde intraflagellar transport (IFT): deletion of DHC1b causes very short flagella, massive redistribution of IFT raft subunits from a peri-basal body pool into flagella, and loss of retrograde IFT movement, while anterograde IFT proceeds. Western blots confirm DHC1b is present in the flagellum in detergent- and ATP-soluble fractions, consistent with its role as the retrograde IFT motor. Genetic deletion mutant characterization, Western blot, immunolocalization, IFT particle redistribution assay The Journal of cell biology High 9971742
1999 CHE-3 (C. elegans DHC1b/DYNC2H1 ortholog) is specifically responsible for retrograde transport of the anterograde IFT motor kinesin-II and its cargo (OSM-1, OSM-6) within sensory cilia but not within dendrites; loss of che-3 inhibits retrograde IFT in cilia while anterograde IFT proceeds normally. Fluorescence microscopy-based transport assay in living C. elegans, che-3 mutant genetic analysis The Journal of cell biology High 10545497
1996 DHC1b (DYNC2H1) is a cytoplasmic dynein isoform expressed in both ciliated and non-ciliated cells; in ciliated rat tracheal epithelial cells, DHC1b protein localizes to the cytoplasm (not to cilia), accumulates at the apical ends of cells, and its expression increases during ciliogenesis, distinguishing it from axonemal dyneins and from conventional cytoplasmic dynein DHC1a. Isoform-specific antibody generation, indirect immunofluorescence microscopy, Western blot, expression during ciliogenesis in cultured rat tracheal epithelial cells Journal of cell science Medium 8832411
2009 Loss-of-function mutations in DYNC2H1 cause skeletal ciliopathy (asphyxiating thoracic dystrophy/short rib-polydactyly syndrome), establishing that DYNC2H1 is directly involved in the generation and maintenance of cilia in humans; cultured chondrocytes from affected individuals show morphologically abnormal, shortened cilia and abnormal cytoskeletal microtubule architecture. Homozygosity mapping, Sanger sequencing, cell morphology analysis of patient-derived chondrocytes (cilia length and microtubule architecture) American journal of human genetics High 19361615 19442771
2013 Loss of DYNC2H1 function results in accumulation of anterograde IFT proteins at ciliary tips in patient fibroblasts, confirming a retrograde IFT defect; missense mutations cluster to functional domains including the ATP motor domain, indicating the motor domain is critical for function. Exome sequencing, SNP mapping, patient fibroblast immunofluorescence showing anterograde IFT protein accumulation at ciliary tips Journal of medical genetics Medium 23456818
2015 In medaka (Oryzias latipes), loss of dhc2 (DYNC2H1 ortholog) causes shortened cilia and partial defects in Hedgehog signaling; Ptch1 receptor localizes exclusively to cilia in fish as in mammals, placing DYNC2H1-dependent retrograde IFT upstream of ciliary Hedgehog signal transduction. Maternal-zygotic mutant generation and phenotypic analysis, immunolocalization of Ptch1 to cilia, Hh pathway gene expression analysis BMC developmental biology Medium 25645819
2019 DYNC2H1 (DHC2) mediates nuclear localization of DNA repair proteins XPC and CBX5; knockdown of DHC2 impairs nuclear transport of XPC and CBX5, leading to increased temozolomide-induced DNA damage in MGMT-deficient glioblastoma cells; this mechanism underlies acquired temozolomide resistance. siRNA knockdown, subcellular proteomics, immunofluorescence of XPC/CBX5 localization, in vitro and in vivo TMZ sensitivity assays Brain : a journal of neurology Medium 31347685
2020 Hypomorphic DYNC2H1 variants (including one disrupting the exon 41 splice donor) impair dynein-2 motility in vitro and perturb IFT88 distribution within cilia; a retina-predominant DYNC2H1 transcript whose expression increases during retinal organoid differentiation was identified, and variants disrupting only this transcript cause nonsyndromic inherited retinal degeneration. In vitro dynein motility assay, fibroblast cilia assay (IFT88 distribution), iPSC-derived retinal organoids, genome/exome sequencing Genetics in medicine High 32753734
2025 Loss of Dync2h1 in NIH/3T3 fibroblasts (Dync2h1-KO) abolishes the production of a cilium-dependent wound-healing secretome; conditioned medium from Dync2h1-KO cells fails to enhance wound healing in primary cilium-deficient fibroblasts, whereas wild-type conditioned medium (enriched in LPC(14:0)) does, placing DYNC2H1-dependent ciliary function upstream of paracrine secretion of LPC(14:0) and ECM-remodeling signals. Dync2h1-KO cell line, conditioned medium transfer assay, fractionation, untargeted metabolomics, transcriptomic profiling bioRxivpreprint Low bio_10.1101_2025.08.20.671189

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The DHC1b (DHC2) isoform of cytoplasmic dynein is required for flagellar assembly. The Journal of cell biology 374 9971742
1999 Role of a class DHC1b dynein in retrograde transport of IFT motors and IFT raft particles along cilia, but not dendrites, in chemosensory neurons of living Caenorhabditis elegans. The Journal of cell biology 242 10545497
2009 DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. American journal of human genetics 176 19442771
2009 Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. American journal of human genetics 114 19361615
2019 Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2. Brain : a journal of neurology 113 31347685
2013 Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. Journal of medical genetics 107 23456818
2017 Linc-DYNC2H1-4 promotes EMT and CSC phenotypes by acting as a sponge of miR-145 in pancreatic cancer cells. Cell death & disease 76 28703793
2012 NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. Journal of medical genetics 53 22499340
1996 A novel cytoplasmic dynein heavy chain: expression of DHC1b in mammalian ciliated epithelial cells. Journal of cell science 48 8832411
2020 DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration. Genetics in medicine : official journal of the American College of Medical Genetics 44 32753734
2005 Structural and biochemical characterization of DHC2, a novel diheme cytochrome c from Geobacter sulfurreducens. Biochemistry 33 16156654
2019 Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma. Neurology 26 31197031
2017 Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino-Noonan type. Clinical genetics 18 27925158
2016 Expression of dynein, cytoplasmic 2, heavy chain 1 (DHC2) associated with glioblastoma cell resistance to temozolomide. Scientific reports 17 27375225
2015 Targeted next-generation sequencing identifies novel compound heterozygous mutations of DYNC2H1 in a fetus with short rib-polydactyly syndrome, type III. Clinica chimica acta; international journal of clinical chemistry 16 25982780
2016 Identification of novel DYNC2H1 mutations associated with short rib-polydactyly syndrome type III using next-generation panel sequencing. Genetics and molecular research : GMR 13 27323140
2018 Prenatal diagnosis of short-rib polydactyly syndrome type III or short-rib thoracic dysplasia 3 with or without polydactyly (SRTD3) associated with compound heterozygous mutations in DYNC2H1 in a fetus. Taiwanese journal of obstetrics & gynecology 12 29458881
2017 DYNC2H1 mutation causes Jeune syndrome and recurrent lung infections associated with ciliopathy. The clinical respiratory journal 11 28257607
2020 Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype? Molecular genetics & genomic medicine 10 31943948
2023 Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome. European journal of human genetics : EJHG 8 36599940
2022 Compound heterozygous variants in DYNC2H1 in a foetus with type III short rib-polydactyly syndrome and situs inversus totalis. BMC medical genomics 8 35277174
2022 Prenatal Diagnosis of Jeune Syndrome Caused by Compound Heterozygous Variants in DYNC2H1 Gene-Case Report with Rapid WES Procedure and Differential Diagnosis of Lethal Skeletal Dysplasias. Genes 7 35893076
2023 RNA sequencing resolves novel DYNC2H1 variants causing short-rib thoracic dysplasia type 3: Case report. Molecular genetics & genomic medicine 6 37489014
2018 Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios. Birth defects research 6 29359448
2008 Pseudo-merohedral twinning in crystals of the dihaem c-type cytochrome DHC2 from Geobacter sulfurreducens. Acta crystallographica. Section D, Biological crystallography 6 18703849
2023 Genetic variations in the DYNC2H1 gene causing SRTD3 (short-rib thoracic dysplasia 3 with or without polydactyly). Frontiers in genetics 5 37091781
2023 Genetic analysis and prenatal diagnosis of short-rib thoracic dysplasia 3 with or without polydactyly caused by compound heterozygous variants of DYNC2H1 gene in four Chinese families. Frontiers in genetics 4 37007936
2023 Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 4 37100787
2021 Radiological and histopathological features of short rib‑polydactyly syndrome type III and identification of two novel DYNC2H1 variants. Molecular medicine reports 4 33846808
2020 Identification of novel compound heterozygous mutations of the DYNC2H1 gene in a fetus with short-rib thoracic dysplasia 3 with or without polydactyly. Intractable & rare diseases research 4 32494556
2022 Pathogenic variant of DYNC2H1 associated with lingual hamartoma in a Chinese pedigree. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 3 36087272
2022 Characterization of a novel deep-intronic variant in DYNC2H1 identified by whole-exome sequencing in a patient with a lethal form of a short-rib thoracic dysplasia type III. Cold Spring Harbor molecular case studies 3 36442996
2025 DYNC2H1 mutation as a potential predictive biomarker for immune checkpoint inhibitor efficacy in NSCLC and melanoma. Investigational new drugs 2 39934438
2022 [Family analysis of a child with Short-rib polydactyly syndrome type III due to variant of DYNC2H1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 35929941
2015 The medaka dhc2 mutant reveals conserved and distinct mechanisms of Hedgehog signaling in teleosts. BMC developmental biology 2 25645819
2024 DYNC2H1 splicing variants causing severe prenatal short-rib polydactyly syndrome and postnatal orofaciodigital syndrome. Annals of human genetics 1 39361243
2019 Generation of an induced pluripotent stem cell line (SDQLCHi003-a) from a patient with short rib-thoracic dysplasia syndrome type III carrying compound heterozygous mutations in DYNC2H1. Stem cell research 1 31415973
2025 A novel compound heterozygous mutation in the DYNC2H1 gene in a Chinese family with Jeune syndrome. Hereditas 0 39881416
2025 Expanding the genetic spectrum of short rib polydactyly syndrome: Novel DYNC2H1 variants and functional insights. Bone 0 40339774
2025 [Clinical characteristics and prenatal diagnosis of a fetus with Short-rib thoracic dysplasia syndrome due to variants of DYNC2H1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 41645379
2024 Whole-Exome Sequencing Identifies DYNC2H1 Mutations as a Cause of Jeune Asphyxiating Thoracic Dystrophy Without Extra-Skeletal Organ Involvement. International medical case reports journal 0 38550721
2019 Attenuated Type of Asphyxiating Thoracic Dysplasia due to Mutations in DYNC2H1 Gene. Prague medical report 0 31935347

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