DYNC1H1 explained

Cytoplasmic dynein 1 heavy chain 1 is a protein that in humans is encoded by the DYNC1H1 gene.[1] [2] [3] 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. 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.[4]  It binds cargo via interaction with other dynein subunits at its N-terminal tail.[5]

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. Other well known adaptors and regulators are Dynactin, PAFAH1B1[6] and CDC5L.[7]

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. Mutations in the DYNC1H1 gene have been associated with epilepsy, neuromuscular disease, brain malformations, intellectual disability, autism, and neurodegenerative diseases.[8] These as a whole are considered to be DYNC1H1-Related Disorders or dyneinopathies.[9]   Recent data implies that DYNC1H1-Related Disorders should be considered progressive, though the trigger and symptoms of that progress vary from patient to patient. As of September 1, 2024, nearly 1900 gene variants have been identified and classified as either pathogenic, likely pathogenic, or variants of unknown significance.[10]   The vast majority of these are missense mutations. Due to a high degree of pleiotropy, the genotype-phenotype spectrum is still developing.[11] Given the heterogeneity of symptoms, large gene size, and the high conservation of the gene,[12] 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.

Prior to genetic testing, clinical diagnoses for these symptoms range from Charcot-Marie-Tooth disease[13] as well as spinal muscular atrophy with lower extremity predominance 1 (SMA-LED1).[14] Another symptom is Autosomal dominant non-syndromic intellectual disability.[15] DYNC1H1 gene variants have been increasingly correlated with Amyotrophic lateral sclerosis,[16] [17] malformations of cortical development, and seizure disorders.[18]   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.[19]

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.

Further reading

Notes and References

  1. Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter ME, Schroer TA, Vaughan KT, Witman GB, King SM, Vallee RB . Cytoplasmic dynein nomenclature . J Cell Biol . 171 . 3 . 411–3 . November 2005 . 16260502 . 2171247 . 10.1083/jcb.200508078 .
  2. Vaisberg EA, Grissom PM, McIntosh JR . Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles . J Cell Biol . 133 . 4 . 831–42 . August 1996 . 8666668 . 2120833 . 10.1083/jcb.133.4.831 .
  3. Web site: Entrez Gene: DYNC1H1 dynein, cytoplasmic 1, heavy chain 1.
  4. Berth SH, Lloyd TE . Disruption of axonal transport in neurodegeneration . The Journal of Clinical Investigation . 133 . 11 . June 2023 . 37259916 . 10232001 . 10.1172/JCI168554 .
  5. Cason SE, Holzbaur EL . Selective motor activation in organelle transport along axons . Nature Reviews. Molecular Cell Biology . 23 . 11 . 699–714 . November 2022 . 35637414 . 10.1038/s41580-022-00491-w .
  6. Tai CY, Dujardin DL, Faulkner NE, Vallee RB . Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function . The Journal of Cell Biology . 156 . 6 . 959–968 . March 2002 . 11889140 . 2173479 . 10.1083/jcb.200109046 .
  7. Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI . Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry . The EMBO Journal . 19 . 23 . 6569–6581 . December 2000 . 11101529 . 305846 . 10.1093/emboj/19.23.6569 .
  8. 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, Lévy J, Capri Y, Scavina M, Körner RW, Valuvullah Z, Weiß C, Möller GM, Thiel M, Sinnema M, Kamsteeg EJ, Donkervoort S, Duboc V, Zaafrane-Khachnaoui K, Elkhateeb N, Selim L, Margot H, Marin V, Beneteau C, Isidor B, Cogne B, Keren B, Küsters B, Beggs AH, Genetti CA, Nicolai J, Dötsch J, Koy A, Bönnemann CG, von der Hagen M, von Kleist-Retzow JC, Voermans N, Jungbluth H, Dafsari HS . The expanding clinical and genetic spectrum of DYNC1H1-related disorders . Brain . June 2024 . 38848546 . 10.1093/brain/awae183 . free .
  9. Marzo MG, Griswold JM, Ruff KM, Buchmeier RE, Fees CP, Markus SM . Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction . eLife . 8 . e47246. July 2019 . 31364990. 6733598 . 10.7554/eLife.47246 . free .
  10. Web site: DYNC1H1 . ClinVar . 2024-10-03 . U.S. National Library of Medicine .
  11. Li JT, Dong SQ, Zhu DQ, Yang WB, Qian T, Liu XN, Chen XJ . Expanding the Phenotypic and Genetic Spectrum of Neuromuscular Diseases Caused by DYNC1H1 Mutations . Frontiers in Neurology . 13 . 943324 . 2022-07-11 . 35899263 . 9309508 . 10.3389/fneur.2022.943324 . free .
  12. Cho C, Vale RD . 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 . January 2012 . 22062687 . 3249483 . 10.1016/j.bbamcr.2011.10.009 .
  13. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S . Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease . American Journal of Human Genetics . 89 . 2 . 308–312 . August 2011 . 21820100 . 3155164 . 10.1016/j.ajhg.2011.07.002 .
  14. 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 . Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy . Neurology . 78 . 22 . 1714–1720 . May 2012 . 22459677 . 3359582 . 10.1212/WNL.0b013e3182556c05 .
  15. Web site: Orphanet: Rare non-syndromic intellectual disability . 2024-10-03 . www.orpha.net.
  16. Zhou Z, Kim J, Huang AY, Nolan M, Park J, Doan R, Shin T, Miller MB, Chhouk B, Morillo K, Yeh RC, Kenny C, Neil JE, Lee CZ, Ohkubo T, Ravits J, Ansorge O, Ostrow LW, Lagier-Tourenne C, Lee EA, Walsh CA . Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations . bioRxiv . December 2023 . 38077003 . 10705414 . 10.1101/2023.11.30.569436 .
  17. Mentis AA, Vlachakis D, Papakonstantinou E, Zaganas I, Patrinos GP, Chrousos GP, Dardiotis E . A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum . Cold Spring Harbor Molecular Case Studies . 8 . 2 . mcs.a006096 . February 2022 . 34535505 . 8958913 . 10.1101/mcs.a006096 .
  18. Cuccurullo C, Cerulli Irelli E, Ugga L, Riva A, D'Amico A, Cabet S, Lesca G, Bilo L, Zara F, Iliescu C, Barca D, Fung F, Helbig K, Ortiz-Gonzalez X, Schelhaas HJ, Willemsen MH, van der Linden I, Canafoglia L, Courage C, Gommaraschi S, Gonzalez-Alegre P, Bardakjian T, Syrbe S, Schuler E, Lemke JR, Vari S, Roende G, Bak M, Huq M, Powis Z, Johannesen KM, Hammer TB, Møller RS, Rabin R, Pappas J, Zupanc ML, Zadeh N, Cohen J, Naidu S, Krey I, Saneto R, Thies J, Licchetta L, Tinuper P, Bisulli F, Minardi R, Bayat A, Villeneuve N, Molinari F, Salimi Dafsari H, Moller B, Le Roux M, Houdayer C, Vecchi M, Mammi I, Fiorini E, Proietti J, Ferri S, Cantalupo G, Battaglia DI, Gambardella ML, Contaldo I, Brogna C, Trivisano M, De Dominicis A, Bova SM, Gardella E, Striano P, Coppola A . Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants . Epilepsia . July 2024 . 38953796. 10.1111/epi.18054 .
  19. Liu W, Cheng M, Zhu Y, Chen Y, Yang Y, Chen H, Niu X, Tian X, Yang X, Zhang Y . DYNC1H1-related epilepsy: Genotype-phenotype correlation . Developmental Medicine and Child Neurology . 65 . 4 . 534–543 . April 2023 . 36175372 . 10.1111/dmcn.15414 .

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