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DYNC1H1

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DYNC1H1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDYNC1H1, DHC1, DHC1a, DNCH1, DNCL, DNECL, DYHC, Dnchc1, HL-3, SMALED1, p22, CMT2O, dynein cytoplasmic 1 heavy chain 1
External IDsOMIM: 600112; MGI: 103147; HomoloGene: 1053; GeneCards: DYNC1H1; OMA:DYNC1H1 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 12: 110.57 – 110.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

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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

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000197102 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b 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. ^ a b 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. ^ a b 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. ^ a b c d 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. ^ a b 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

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