DYNC1H1

DYNC1H1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2BOR, 2BOT
Identifiers
Aliases	DYNC1H1 , DHC1, DHC1a, DNCH1, DNCL, DNECL, DYHC, Dnchc1, HL-3, SMALED1, p22, CMT2O, dynein cytoplasmic 1 heavy chain 1
External IDs	OMIM: 600112; MGI: 103147; HomoloGene: 1053; GeneCards: DYNC1H1; OMA:DYNC1H1 - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q32.31 Start 101,964,573 bp [1] End 102,056,443 bp [1]
Gene location (Mouse) Chr. Chromosome 12 (mouse) [2] Band 12 F1|12 60.7 cM Start 110,567,886 bp [2] End 110,633,379 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence ventricular zone prefrontal cortex stromal cell of endometrium right frontal lobe right hemisphere of cerebellum Brodmann area 9 postcentral gyrus lateral nuclear group of thalamus C1 segment Top expressed in dentate gyrus of hippocampal formation granule cell primary visual cortex CA3 field entorhinal cortex superior frontal gyrus perirhinal cortex ventricular zone external carotid artery central gray substance of midbrain facial motor nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function microtubule motor activity nucleotide binding ATPase activity protein binding dynein light intermediate chain binding cytoskeletal motor activity ATP binding RNA binding minus-end-directed microtubule motor activity dynein light chain binding dynein intermediate chain binding Cellular component cytoplasm cytosol centrosome membrane filopodium cytoplasmic dynein complex dynein complex microtubule extracellular exosome cytoskeleton extracellular matrix extracellular region azurophil granule lumen cytoplasmic microtubule cell cortex axon cytoplasm Biological process antigen processing and presentation of exogenous peptide antigen via MHC class II establishment of spindle localization mitotic spindle organization endoplasmic reticulum to Golgi vesicle-mediated transport microtubule-based movement G2/M transition of mitotic cell cycle P-body assembly stress granule assembly neutrophil degranulation ciliary basal body-plasma membrane docking regulation of mitotic spindle organization positive regulation of intracellular transport regulation of metaphase plate congression positive regulation of spindle assembly cytoplasmic microtubule organization minus-end-directed vesicle transport along microtubule cell cycle cell division sister chromatid cohesion regulation of G2/M transition of mitotic cell cycle transport positive regulation of cold-induced thermogenesis mitotic cell cycle nuclear migration retrograde axonal transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1778 13424 Ensembl ENSG00000197102 ENSMUSG00000018707 UniProt Q14204 Q9JHU4 RefSeq (mRNA) NM_001376 NM_030238 RefSeq (protein) NP_001367 NP_084514 Location (UCSC) Chr 14: 101.96 – 102.06 Mb Chr 12: 110.57 – 110.63 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytoplasmic dynein 1 heavy chain 1 is a protein that in humans is encoded by the DYNC1H1 gene. ^{[5] [6] [7]} Dynein is a molecular motor protein that is responsible for the transport of numerous cellular cargoes to minus ends of microtubules, which are typically found in the center of a cell, or the cell body of neurons. It is located on the 14th chromosome at position 14q32.31. ^[5] Cytoplasmic dynein transports cargoes along the axon in the retrograde direction, bringing materials from the axon to the cell body. Dynein heavy chain binds microtubules and hydrolyzes ATP at its C-terminal head. ^[8]  It binds cargo via interaction with other dynein subunits at its N-terminal tail. ^[9]

Interactions

DYNC1H1 has been shown to interact with a large variety of proteins that act as adaptors and regulators. The dynein motor protein complex itself is a large, 1.4 MDa multimeric complex composed of dimerized heavy chains, two intermediate chains, two light intermediate chains, and additional light chains. ^[8]  Other well known adaptors and regulators are Dynactin, PAFAH1B1 ^[10] and CDC5L. ^[11]

Clinical relevance

Defects in axonal transport, of which dynein plays a key role, have been implicated in conditions ranging from developmental defects in the brain to neurodegenerative disease. ^[9] Mutations in the DYNC1H1 gene have been associated with epilepsy, neuromuscular disease, brain malformations, intellectual disability, autism, and neurodegenerative diseases. ^[12] These as a whole are considered to be DYNC1H1-Related Disorders ^[12] or dyneinopathies ^[13] .  Recent data implies that DYNC1H1-Related Disorders should be considered progressive, though the trigger and symptoms of that progress vary from patient to patient. ^[12] As of September 1, 2024, nearly 1900 gene variants have been identified and classified as either pathogenic, likely pathogenic, or variants of unknown significance. ^[14]   The vast majority of these are missense mutations. Due to a high degree of pleiotropy, the genotype-phenotype spectrum is still developing. ^[15] Given the heterogeneity of symptoms, large gene size, and the high conservation of the gene ^[16] , it is likely that many patients remain undiagnosed.  In recent larger cohort studies, the average age of patients was only 12 years old, likely due to symptoms overlap with other disorders like cerebral palsy and idiopathic autism and intellectual disability. ^[12]

Prior to genetic testing, clinical diagnoses for these symptoms range from Charcot-Marie-Tooth disease ^[17] as well as spinal muscular atrophy with lower extremity predominance 1 (SMA-LED1). ^[18] Another symptom is Autosomal dominant non-syndromic intellectual disability. ^[19] DYNC1H1 gene variants have been increasingly correlated with Amyotrophic lateral sclerosis ^{[20] [21]} , malformations of cortical development, and seizure disorders. ^[22]   It is estimated that roughly 40% of patients with DYNC1H1 gene variants have epilepsy, and 80-92% of those with DYNC1H1-related epilepsy have malformations of cortical development, including both lissencephaly and polymicrogyria. ^{[22] [23]}

Society and Culture

The DYNC1H1 Association (dync1h1.org), a non-profit patient advocacy organization, was founded in 2023 with the goal of accelerating research into treatments for DYNC1H1-related disorders. The three founders are parents of children who have DYNC1H1-related disorders.

References

1. GRCh38: Ensembl release 89: ENSG00000197102 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000018707 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter ME, Schroer TA, Vaughan KT, Witman GB, King SM, Vallee RB (November 2005). "Cytoplasmic dynein nomenclature". J Cell Biol. 171 (3): 411–3. doi:10.1083/jcb.200508078. PMC   2171247 . PMID   16260502.
6. Vaisberg EA, Grissom PM, McIntosh JR (August 1996). "Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles". J Cell Biol. 133 (4): 831–42. doi:10.1083/jcb.133.4.831. PMC   2120833 . PMID   8666668.
7. "Entrez Gene: DYNC1H1 dynein, cytoplasmic 1, heavy chain 1".
8. Berth SH, Lloyd TE (2023-06-01). "Disruption of axonal transport in neurodegeneration". The Journal of Clinical Investigation. 133 (11). doi:10.1172/JCI168554. ISSN   0021-9738. PMC   10232001 . PMID   37259916.
9. Cason SE, Holzbaur EL (2022-05-30). "Selective motor activation in organelle transport along axons". Nature Reviews Molecular Cell Biology. 23 (11): 699–714. doi:10.1038/s41580-022-00491-w. ISSN   1471-0080. PMID   35637414.
10. Tai CY, Dujardin Denis L, Faulkner Nicole E, Vallee Richard B (March 2002). "Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function". J. Cell Biol. 156 (6). United States: 959–68. doi:10.1083/jcb.200109046. ISSN   0021-9525. PMC   2173479 . PMID   11889140.
11. Ajuh P, Kuster B, Panov K, Zomerdijk J C, Mann M, Lamond A I (December 2000). "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". EMBO J. 19 (23). ENGLAND: 6569–81. doi:10.1093/emboj/19.23.6569. ISSN   0261-4189. PMC   305846 . PMID   11101529.
12. Möller B, Becker LL, Saffari A, Afenjar A, Coci EG, Williamson R, Ward-Melver C, Gibaud M, Sedláčková L, Laššuthová P, Libá Z, Vlčková M, William N, Klee EW, Gavrilova RH (2024-06-08). "The expanding clinical and genetic spectrum of DYNC1H1-related disorders". Brain. doi:10.1093/brain/awae183. ISSN   0006-8950. PMID   38848546.
13. Marzo, M. G., Griswold, J. M., Ruff, K. M., Buchmeier, R. E., Fees, C. P., & Markus, S. M. (2019). Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction. Elife, 8, e47246.
14. "ClinVar". www.ncbi.nlm.nih.gov. Retrieved 2024-10-03.
15. Li JT, Dong SQ, Zhu DQ, Yang WB, Qian T, Liu XN, Chen XJ (2022-07-11). "Expanding the Phenotypic and Genetic Spectrum of Neuromuscular Diseases Caused by DYNC1H1 Mutations". Frontiers in Neurology. 13. doi: 10.3389/fneur.2022.943324 . ISSN   1664-2295. PMC   9309508 . PMID   35899263.
16. Cho C, Vale RD (2012-01-01). "The mechanism of dynein motility: Insight from crystal structures of the motor domain". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (1): 182–191. doi:10.1016/j.bbamcr.2011.10.009. PMC   3249483 . PMID   22062687.
17. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S (August 2011). "Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease". Am. J. Hum. Genet. 89 (2): 308–12. doi:10.1016/j.ajhg.2011.07.002. PMC   3155164 . PMID   21820100.
18. Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S, Ma D, Masi S, Allred P, Al-Lozi M, Reilly MM, Miller LJ, Jani-Acsadi A, Pestronk A, Shy ME, Muntoni F, Vallee RB, Baloh RH (2012). "Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy". Neurology. 78 (16): 1714–1720. doi:10.1212/WNL.0b013e3182556c05. PMC   3359582 . PMID   22459677.
19. "Orphanet: Rare non-syndromic intellectual disability". www.orpha.net. Retrieved 2024-10-03.
20. Zhou Z, Kim J, Huang AY, Nolan M, Park J, Doan R, Shin T, Miller MB, Chhouk B (2023-12-01), Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations, doi:10.1101/2023.11.30.569436, PMC   10705414 , PMID   38077003 , retrieved 2024-10-03
21. Mentis AF, Vlachakis D, Papakonstantinou E, Zaganas I, Patrinos GP, Chrousos GP, Dardiotis E (2021-09-17). "A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum". Molecular Case Studies: mcs.a006096. doi:10.1101/mcs.a006096. ISSN   2373-2865. PMC   8958913 . PMID   34535505.
22. Cuccurullo, C., Cerulli Irelli, E., Ugga, L., Riva, A., D'Amico, A., Cabet, S., ... & Coppola, A. (2024). Clinical features and genotype–phenotype correlations in epilepsy patients with de novo DYNC1H1 variants. Epilepsia.
23. Liu W, Cheng M, Zhu Y, Chen Y, Yang Y, Chen H, Niu X, Tian X, Yang X, Zhang Y (2022-09-29). "DYNC1H1 -related epilepsy: Genotype–phenotype correlation". Developmental Medicine & Child Neurology. 65 (4): 534–543. doi:10.1111/dmcn.15414. ISSN   0012-1622.

Further reading

• Narayan D, Desai T, Banks A, et al. (1995). "Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization". Genomics. 22 (3): 660–1. doi: 10.1006/geno.1994.1447 . PMID   8001984.
• Vaisberg EA, Koonce MP, McIntosh JR (1993). "Cytoplasmic dynein plays a role in mammalian mitotic spindle formation". J. Cell Biol. 123 (4): 849–58. doi:10.1083/jcb.123.4.849. PMC   2200153 . PMID   8227145.
• Vaughan KT, Mikami A, Paschal BM, et al. (1997). "Multiple mouse chromosomal loci for dynein-based motility". Genomics. 36 (1): 29–38. doi:10.1006/geno.1996.0422. PMID   8812413.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi: 10.1101/gr.6.9.791 . PMID   8889548.
• Nagase T, Ishikawa K, Nakajima D, et al. (1997). "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Res. 4 (2): 141–50. doi: 10.1093/dnares/4.2.141 . PMID   9205841.
• Neesen J, Koehler MR, Kirschner R, et al. (1997). "Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene". Gene. 200 (1–2): 193–202. doi:10.1016/S0378-1119(97)00417-4. PMID   9373155.
• Byers HR, Yaar M, Eller MS, et al. (2000). "Role of cytoplasmic dynein in melanosome transport in human melanocytes". J. Invest. Dermatol. 114 (5): 990–7. doi: 10.1046/j.1523-1747.2000.00957.x . PMID   10771482.
• Habermann A, Schroer TA, Griffiths G, Burkhardt JK (2001). "Immunolocalization of cytoplasmic dynein and dynactin subunits in cultured macrophages: enrichment on early endocytic organelles". J. Cell Sci. 114 (Pt 1): 229–240. doi:10.1242/jcs.114.1.229. PMID   11112706.
• Sasaki S, Shionoya A, Ishida M, et al. (2001). "A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system". Neuron. 28 (3): 681–96. doi: 10.1016/S0896-6273(00)00146-X . PMID   11163259.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• Payne C, Rawe V, Ramalho-Santos J, et al. (2004). "Preferentially localized dynein and perinuclear dynactin associate with nuclear pore complex proteins to mediate genomic union during mammalian fertilization". J. Cell Sci. 116 (Pt 23): 4727–38. doi:10.1242/jcs.00784. PMID   14600259. S2CID   20578326.
• Byers HR, Maheshwary S, Amodeo DM, Dykstra SG (2003). "Role of cytoplasmic dynein in perinuclear aggregation of phagocytosed melanosomes and supranuclear melanin cap formation in human keratinocytes". J. Invest. Dermatol. 121 (4): 813–20. doi: 10.1046/j.1523-1747.2003.12481.x . PMID   14632200.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi: 10.1038/ng1285 . PMID   14702039.
• Navarro-Lérida I, Martínez Moreno M, Roncal F, et al. (2004). "Proteomic identification of brain proteins that interact with dynein light chain LC8". Proteomics. 4 (2): 339–46. doi:10.1002/pmic.200300528. PMID   14760703. S2CID   8868600.
• Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC   442148 . PMID   15231748.
• Jin J, Smith FD, Stark C, et al. (2004). "Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization". Curr. Biol. 14 (16): 1436–50. Bibcode:2004CBio...14.1436J. doi: 10.1016/j.cub.2004.07.051 . PMID   15324660. S2CID   2371325.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC   528928 . PMID   15489334.
• Andersen JS, Lam YW, Leung AK, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. Bibcode:2005Natur.433...77A. doi:10.1038/nature03207. PMID   15635413. S2CID   4344740.

External links

• Overview of all the structural information available in the PDB for UniProt : Q14204 (Cytoplasmic dynein 1 heavy chain 1) at the PDBe-KB .