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{{Short description|Protein-coding gene in the species Homo sapiens}}
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'''Cytoplasmic dynein 1 heavy chain 1''' is a [[protein]] that in humans is encoded by the ''DYNC1H1'' [[gene]].<ref name="pmid16260502">{{cite journal | vauthors = Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter ME, Schroer TA, Vaughan KT, Witman GB, King SM, Vallee RB | title = Cytoplasmic dynein nomenclature | journal = J Cell Biol | volume = 171 | issue = 3 | pages = 411–3 |date=November 2005 | pmid = 16260502 | pmc = 2171247 | doi = 10.1083/jcb.200508078 }}</ref><ref name="pmid8666668">{{cite journal | vauthors = Vaisberg EA, Grissom PM, McIntosh JR | title = Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles | journal = J Cell Biol | volume = 133 | issue = 4 | pages = 831–42 |date=August 1996 | pmid = 8666668 | pmc = 2120833 | doi =10.1083/jcb.133.4.831 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DYNC1H1 dynein, cytoplasmic 1, heavy chain 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1778| accessdate = }}</ref>
'''Cytoplasmic dynein 1 heavy chain 1''' is a [[protein]] that in humans is encoded by the ''DYNC1H1'' [[gene]].<ref name="pmid16260502">{{cite journal | vauthors = Pfister KK, Fisher EM, Gibbons IR, Hays TS, Holzbaur EL, McIntosh JR, Porter ME, Schroer TA, Vaughan KT, Witman GB, King SM, Vallee RB | title = Cytoplasmic dynein nomenclature | journal = J Cell Biol | volume = 171 | issue = 3 | pages = 411–3 |date=November 2005 | pmid = 16260502 | pmc = 2171247 | doi = 10.1083/jcb.200508078 }}</ref><ref name="pmid8666668">{{cite journal | vauthors = Vaisberg EA, Grissom PM, McIntosh JR | title = Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles | journal = J Cell Biol | volume = 133 | issue = 4 | pages = 831–42 |date=August 1996 | pmid = 8666668 | pmc = 2120833 | doi =10.1083/jcb.133.4.831 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DYNC1H1 dynein, cytoplasmic 1, heavy chain 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1778}}</ref> 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.<ref name="pmid16260502" /> 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.<ref name="Berth_2023">{{cite journal | vauthors = Berth SH, Lloyd TE | title = Disruption of axonal transport in neurodegeneration | journal = The Journal of Clinical Investigation | volume = 133 | issue = 11 | date = June 2023 | pmid = 37259916 | pmc = 10232001 | doi = 10.1172/JCI168554 }}</ref> It binds cargo via interaction with other dynein subunits at its N-terminal tail.<ref name="Cason_2022">{{cite journal | vauthors = Cason SE, Holzbaur EL | title = Selective motor activation in organelle transport along axons | journal = Nature Reviews. Molecular Cell Biology | volume = 23 | issue = 11 | pages = 699–714 | date = November 2022 | pmid = 35637414 | doi = 10.1038/s41580-022-00491-w }}</ref>

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==Interactions==
==Interactions==
DYNC1H1 has been shown to [[Protein-protein interaction|interact]] with [[PAFAH1B1]]<ref name=pmid11889140>{{cite journal |last=Tai |first=Chin-Yin |author2=Dujardin Denis L |author3=Faulkner Nicole E |author4=Vallee Richard B |date=March 2002 |title=Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function |journal=J. Cell Biol. |volume=156 |issue=6 |pages=959–68 |publisher= |location = United States| issn = 0021-9525| pmid = 11889140 |doi = 10.1083/jcb.200109046 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=2173479 }}</ref> and [[CDC5L]].<ref name=pmid11101529>{{cite journal |last=Ajuh |first=P |author2=Kuster B |author3=Panov K |author4=Zomerdijk J C |author5=Mann M |author6=Lamond A I |date=December 2000 |title=Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry |journal=EMBO J. |volume=19 |issue=23 |pages=6569–81 |publisher= |location = ENGLAND| issn = 0261-4189| pmid = 11101529 |doi = 10.1093/emboj/19.23.6569 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |pmc=305846 }}</ref>
DYNC1H1 has been shown to [[Protein-protein interaction|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.<ref name="Berth_2023" /> Other well known adaptors and regulators are Dynactin, [[PAFAH1B1]]<ref name=pmid11889140>{{cite journal | vauthors = Tai CY, Dujardin DL, Faulkner NE, Vallee RB | title = Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function | journal = The Journal of Cell Biology | volume = 156 | issue = 6 | pages = 959–968 | date = March 2002 | pmid = 11889140 | pmc = 2173479 | doi = 10.1083/jcb.200109046 }}</ref> and [[CDC5L]].<ref name=pmid11101529>{{cite journal | vauthors = Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI | title = Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry | journal = The EMBO Journal | volume = 19 | issue = 23 | pages = 6569–6581 | date = December 2000 | pmid = 11101529 | pmc = 305846 | doi = 10.1093/emboj/19.23.6569 }}</ref>


==Clinical relevance==
== 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.<ref name="Cason_2022" /> Mutations in the DYNC1H1 gene have been associated with epilepsy, neuromuscular disease, brain malformations, intellectual disability, autism, and neurodegenerative diseases.<ref name="Möller_2024">{{cite journal | vauthors = 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 | title = The expanding clinical and genetic spectrum of DYNC1H1-related disorders | journal = Brain | date = June 2024 | pmid = 38848546 | doi = 10.1093/brain/awae183 | doi-access = free }}</ref> These as a whole are considered to be DYNC1H1-Related Disorders<ref name="Möller_2024" /> or dyneinopathies.<ref name="pmid">{{cite journal | vauthors = Marzo MG, Griswold JM, Ruff KM, Buchmeier RE, Fees CP, Markus SM | title = Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction | journal = eLife | volume = 8 | issue = | pages = e47246| date = July 2019 | pmid = 31364990| pmc = 6733598 | doi = 10.7554/eLife.47246 | doi-access = free | url = }}</ref>  Recent data implies that DYNC1H1-Related Disorders should be considered progressive, though the trigger and symptoms of that progress vary from patient to patient.<ref name="Möller_2024" /> As of September 1, 2024, nearly 1900 gene variants have been identified and classified as either pathogenic, likely pathogenic, or variants of unknown significance.<ref>{{Cite web | title = DYNC1H1 | work = ClinVar |url=https://www.ncbi.nlm.nih.gov/clinvar/?term=DYNC1H1%5Bgene%5D&redir=gene/ |access-date=2024-10-03 |publisher = U.S. National Library of Medicine }}</ref>  The vast majority of these are missense mutations. Due to a high degree of pleiotropy, the genotype-phenotype spectrum is still developing.<ref>{{cite journal | vauthors = Li JT, Dong SQ, Zhu DQ, Yang WB, Qian T, Liu XN, Chen XJ | title = Expanding the Phenotypic and Genetic Spectrum of Neuromuscular Diseases Caused by <i>DYNC1H1</i> Mutations | journal = Frontiers in Neurology | volume = 13 | pages = 943324 | date = 2022-07-11 | pmid = 35899263 | pmc = 9309508 | doi = 10.3389/fneur.2022.943324 | doi-access = free }}</ref> Given the heterogeneity of symptoms, large gene size, and the high conservation of the gene,<ref>{{cite journal | vauthors = Cho C, Vale RD | title = The mechanism of dynein motility: insight from crystal structures of the motor domain | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1823 | issue = 1 | pages = 182–191 | date = January 2012 | pmid = 22062687 | pmc = 3249483 | doi = 10.1016/j.bbamcr.2011.10.009 }}</ref> 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.<ref name="Möller_2024" />
Mutations in this gene have been shown to cause dominant axonal [[Charcot-Marie-Tooth]] disease<ref name="pmid21820100">{{cite journal | vauthors = Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S | title = Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease | journal = Am. J. Hum. Genet. | volume = 89 | issue = 2 | pages = 308–12 |date=August 2011 | pmid = 21820100 | pmc = 3155164 | doi = 10.1016/j.ajhg.2011.07.002 }}</ref> as well as [[spinal muscular atrophy with lower extremity predominance]] (SMA-LED).<ref>{{cite journal | vauthors = 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 | year = 2012 | title = Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy | journal = Neurology | volume = 78 | issue = 16 | pages = | doi = 10.1212/WNL.0b013e3182556c05 | pmid = 22459677 | url = | format = | accessdate = | pmc = 3359582}}</ref>


Prior to genetic testing, clinical diagnoses for these symptoms range from [[Charcot-Marie-Tooth]] disease<ref name="pmid21820100">{{cite journal | vauthors = Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S | title = Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease | journal = American Journal of Human Genetics | volume = 89 | issue = 2 | pages = 308–312 | date = August 2011 | pmid = 21820100 | pmc = 3155164 | doi = 10.1016/j.ajhg.2011.07.002 }}</ref> as well as [[spinal muscular atrophy with lower extremity predominance 1]] (SMA-LED1).<ref>{{cite journal | vauthors = 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 | title = Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy | journal = Neurology | volume = 78 | issue = 22 | pages = 1714–1720 | date = May 2012 | pmid = 22459677 | pmc = 3359582 | doi = 10.1212/WNL.0b013e3182556c05 }}</ref> Another symptom is Autosomal dominant non-syndromic intellectual disability.<ref>{{Cite web |title=Orphanet: Rare non-syndromic intellectual disability |url=https://www.orpha.net/en/disease/detail/101685 |access-date=2024-10-03 |website=www.orpha.net}}</ref> DYNC1H1 gene variants have been increasingly correlated with Amyotrophic lateral sclerosis,<ref>{{cite journal | vauthors = 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 | title = Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations | journal = bioRxiv | date = December 2023 | pmid = 38077003 | pmc = 10705414 | doi = 10.1101/2023.11.30.569436 }}</ref><ref>{{cite journal | vauthors = Mentis AA, Vlachakis D, Papakonstantinou E, Zaganas I, Patrinos GP, Chrousos GP, Dardiotis E | title = A novel variant in <i>DYNC1H1</i> could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum | journal = Cold Spring Harbor Molecular Case Studies | volume = 8 | issue = 2 | pages = mcs.a006096 | date = February 2022 | pmid = 34535505 | pmc = 8958913 | doi = 10.1101/mcs.a006096 }}</ref> malformations of cortical development, and seizure disorders.<ref name="Cuccurullo_2024">{{cite journal | vauthors = 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 | title = Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants | journal = Epilepsia | volume = | issue = | pages = | date = July 2024 | pmid = 38953796| doi = 10.1111/epi.18054 | url = }}</ref>  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.<ref name="Cuccurullo_2024" /><ref>{{cite journal | vauthors = Liu W, Cheng M, Zhu Y, Chen Y, Yang Y, Chen H, Niu X, Tian X, Yang X, Zhang Y | title = DYNC1H1-related epilepsy: Genotype-phenotype correlation | journal = Developmental Medicine and Child Neurology | volume = 65 | issue = 4 | pages = 534–543 | date = April 2023 | pmid = 36175372 | doi = 10.1111/dmcn.15414 }}</ref>

== Society and Culture ==
The DYNC1H1 Association ([https://dync1h1.org 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==
==References==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
* {{cite journal | vauthors = Narayan D, Desai T, Banks A, Patanjali SR, Ravikumar TS, Ward DC | title = Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization | journal = Genomics | volume = 22 | issue = 3 | pages = 660–661 | date = August 1994 | pmid = 8001984 | doi = 10.1006/geno.1994.1447 | doi-access = free }}
{{PBB_Further_reading
* {{cite journal | vauthors = Vaisberg EA, Koonce MP, McIntosh JR | title = Cytoplasmic dynein plays a role in mammalian mitotic spindle formation | journal = The Journal of Cell Biology | volume = 123 | issue = 4 | pages = 849–858 | date = November 1993 | pmid = 8227145 | pmc = 2200153 | doi = 10.1083/jcb.123.4.849 }}
| citations =
*{{cite journal | vauthors=Narayan D, Desai T, Banks A |title=Localization of the human cytoplasmic dynein heavy chain (DNECL) to 14qter by fluorescence in situ hybridization. |journal=Genomics |volume=22 |issue= 3 |pages= 660–1 |year= 1995 |pmid= 8001984 |doi= 10.1006/geno.1994.1447 |display-authors=etal}}
* {{cite journal | vauthors = Vaughan KT, Mikami A, Paschal BM, Holzbaur EL, Hughes SM, Echeverri CJ, Moore KJ, Gilbert DJ, Copeland NG, Jenkins NA, Vallee RB | title = Multiple mouse chromosomal loci for dynein-based motility | journal = Genomics | volume = 36 | issue = 1 | pages = 29–38 | date = August 1996 | pmid = 8812413 | doi = 10.1006/geno.1996.0422 }}
*{{cite journal | vauthors=Vaisberg EA, Koonce MP, McIntosh JR |title=Cytoplasmic dynein plays a role in mammalian mitotic spindle formation. |journal=J. Cell Biol. |volume=123 |issue= 4 |pages= 849–58 |year= 1993 |pmid= 8227145 |doi=10.1083/jcb.123.4.849 | pmc=2200153 }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 | doi-access = free }}
*{{cite journal | vauthors=Vaughan KT, Mikami A, Paschal BM |title=Multiple mouse chromosomal loci for dynein-based motility. |journal=Genomics |volume=36 |issue= 1 |pages= 29–38 |year= 1997 |pmid= 8812413 |doi= 10.1006/geno.1996.0422 |display-authors=etal}}
*{{cite journal | vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 }}
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*{{cite journal | vauthors=Nagase T, Ishikawa K, Nakajima D |title=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. |journal=DNA Res. |volume=4 |issue= 2 |pages= 141–50 |year= 1997 |pmid= 9205841 |doi=10.1093/dnares/4.2.141 |display-authors=etal}}
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*{{cite journal | vauthors=Neesen J, Koehler MR, Kirschner R |title=Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene. |journal=Gene |volume=200 |issue= 1-2 |pages= 193–202 |year= 1997 |pmid= 9373155 |doi=10.1016/S0378-1119(97)00417-4 |display-authors=etal}}
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*{{cite journal | vauthors=Byers HR, Yaar M, Eller MS |title=Role of cytoplasmic dynein in melanosome transport in human melanocytes. |journal=J. Invest. Dermatol. |volume=114 |issue= 5 |pages= 990–7 |year= 2000 |pmid= 10771482 |doi= 10.1046/j.1523-1747.2000.00957.x |display-authors=etal}}
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*{{cite journal | vauthors=Habermann A, Schroer TA, Griffiths G, Burkhardt JK |title=Immunolocalization of cytoplasmic dynein and dynactin subunits in cultured macrophages: enrichment on early endocytic organelles. |journal=J. Cell Sci. |volume=114 |issue= Pt 1 |pages= 229–240 |year= 2001 |pmid= 11112706 |doi= }}
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*{{cite journal | vauthors=Sasaki S, Shionoya A, Ishida M |title=A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. |journal=Neuron |volume=28 |issue= 3 |pages= 681–96 |year= 2001 |pmid= 11163259 |doi=10.1016/S0896-6273(00)00146-X |display-authors=etal}}
*{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |display-authors=etal|bibcode=2002PNAS...9916899M }}
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*{{cite journal | vauthors=Payne C, Rawe V, Ramalho-Santos J |title=Preferentially localized dynein and perinuclear dynactin associate with nuclear pore complex proteins to mediate genomic union during mammalian fertilization. |journal=J. Cell Sci. |volume=116 |issue= Pt 23 |pages= 4727–38 |year= 2004 |pmid= 14600259 |doi= 10.1242/jcs.00784 |display-authors=etal}}
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*{{cite journal | vauthors=Byers HR, Maheshwary S, Amodeo DM, Dykstra SG |title=Role of cytoplasmic dynein in perinuclear aggregation of phagocytosed melanosomes and supranuclear melanin cap formation in human keratinocytes. |journal=J. Invest. Dermatol. |volume=121 |issue= 4 |pages= 813–20 |year= 2003 |pmid= 14632200 |doi= 10.1046/j.1523-1747.2003.12481.x }}
*{{cite journal | vauthors=Ota T, Suzuki Y, Nishikawa T |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 |display-authors=etal}}
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*{{cite journal | vauthors=Navarro-Lérida I, Martínez Moreno M, Roncal F |title=Proteomic identification of brain proteins that interact with dynein light chain LC8. |journal=Proteomics |volume=4 |issue= 2 |pages= 339–46 |year= 2004 |pmid= 14760703 |doi= 10.1002/pmic.200300528 |display-authors=etal}}
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*{{cite journal | vauthors=Colland F, Jacq X, Trouplin V |title=Functional proteomics mapping of a human signaling pathway. |journal=Genome Res. |volume=14 |issue= 7 |pages= 1324–32 |year= 2004 |pmid= 15231748 |doi= 10.1101/gr.2334104 | pmc=442148 |display-authors=etal}}
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*{{cite journal | vauthors=Jin J, Smith FD, Stark C |title=Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. |journal=Curr. Biol. |volume=14 |issue= 16 |pages= 1436–50 |year= 2004 |pmid= 15324660 |doi= 10.1016/j.cub.2004.07.051 |display-authors=etal}}
*{{cite journal | vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 | pmc=528928 |display-authors=etal}}
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*{{cite journal | vauthors=Andersen JS, Lam YW, Leung AK |title=Nucleolar proteome dynamics. |journal=Nature |volume=433 |issue= 7021 |pages= 77–83 |year= 2005 |pmid= 15635413 |doi= 10.1038/nature03207 |display-authors=etal|bibcode=2005Natur.433...77A }}
}}
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{{refend}}


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* {{cite journal | vauthors = Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = 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 | journal = DNA Research | volume = 4 | issue = 2 | pages = 141–150 | date = April 1997 | pmid = 9205841 | doi = 10.1093/dnares/4.2.141 | doi-access = free }}
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* {{cite journal | vauthors = Neesen J, Koehler MR, Kirschner R, Steinlein C, Kreutzberger J, Engel W, Schmid M | title = Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene | journal = Gene | volume = 200 | issue = 1–2 | pages = 193–202 | date = October 1997 | pmid = 9373155 | doi = 10.1016/S0378-1119(97)00417-4 }}
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* {{cite journal | vauthors = Byers HR, Yaar M, Eller MS, Jalbert NL, Gilchrest BA | title = Role of cytoplasmic dynein in melanosome transport in human melanocytes | journal = The Journal of Investigative Dermatology | volume = 114 | issue = 5 | pages = 990–997 | date = May 2000 | pmid = 10771482 | doi = 10.1046/j.1523-1747.2000.00957.x | doi-access = free }}
⚫
* {{cite journal | vauthors = Habermann A, Schroer TA, Griffiths G, Burkhardt JK | title = Immunolocalization of cytoplasmic dynein and dynactin subunits in cultured macrophages: enrichment on early endocytic organelles | journal = Journal of Cell Science | volume = 114 | issue = Pt 1 | pages = 229–240 | date = January 2001 | pmid = 11112706 | doi = 10.1242/jcs.114.1.229 }}
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* {{cite journal | vauthors = Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A, Hirotsune S | title = A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system | journal = Neuron | volume = 28 | issue = 3 | pages = 681–696 | date = December 2000 | pmid = 11163259 | doi = 10.1016/S0896-6273(00)00146-X | doi-access = free }}
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* {{cite journal | vauthors = Payne C, Rawe V, Ramalho-Santos J, Simerly C, Schatten G | title = Preferentially localized dynein and perinuclear dynactin associate with nuclear pore complex proteins to mediate genomic union during mammalian fertilization | journal = Journal of Cell Science | volume = 116 | issue = Pt 23 | pages = 4727–4738 | date = December 2003 | pmid = 14600259 | doi = 10.1242/jcs.00784 | s2cid = 20578326 | doi-access = }}
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* {{cite journal | vauthors = Byers HR, Maheshwary S, Amodeo DM, Dykstra SG | title = Role of cytoplasmic dynein in perinuclear aggregation of phagocytosed melanosomes and supranuclear melanin cap formation in human keratinocytes | journal = The Journal of Investigative Dermatology | volume = 121 | issue = 4 | pages = 813–820 | date = October 2003 | pmid = 14632200 | doi = 10.1046/j.1523-1747.2003.12481.x | doi-access = free }}
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* {{cite journal | vauthors = Navarro-Lérida I, Martínez Moreno M, Roncal F, Gavilanes F, Albar JP, Rodríguez-Crespo I | title = Proteomic identification of brain proteins that interact with dynein light chain LC8 | journal = Proteomics | volume = 4 | issue = 2 | pages = 339–346 | date = February 2004 | pmid = 14760703 | doi = 10.1002/pmic.200300528 | s2cid = 8868600 }}
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* {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–1332 | date = July 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
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* {{cite journal | vauthors = Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T | title = Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization | journal = Current Biology | volume = 14 | issue = 16 | pages = 1436–1450 | date = August 2004 | pmid = 15324660 | doi = 10.1016/j.cub.2004.07.051 | s2cid = 2371325 | doi-access = free | bibcode = 2004CBio...14.1436J }}
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* {{cite journal | vauthors = Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M | title = Nucleolar proteome dynamics | journal = Nature | volume = 433 | issue = 7021 | pages = 77–83 | date = January 2005 | pmid = 15635413 | doi = 10.1038/nature03207 | s2cid = 4344740 | bibcode = 2005Natur.433...77A }}
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{{refend}}


== External links ==
* {{PDBe-KB2|Q14204|Cytoplasmic dynein 1 heavy chain 1}}


{{gene-14-stub}}
{{gene-14-stub}}

Latest revision as of 03:21, 11 November 2024

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

[edit]

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

[edit]

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

[edit]

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

[edit]
  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, et al. (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 (June 2023). "Disruption of axonal transport in neurodegeneration". The Journal of Clinical Investigation. 133 (11). doi:10.1172/JCI168554. PMC 10232001. PMID 37259916.
  9. ^ a b Cason SE, Holzbaur EL (November 2022). "Selective motor activation in organelle transport along axons". Nature Reviews. Molecular Cell Biology. 23 (11): 699–714. doi:10.1038/s41580-022-00491-w. PMID 35637414.
  10. ^ Tai CY, Dujardin DL, Faulkner NE, Vallee RB (March 2002). "Role of dynein, dynactin, and CLIP-170 interactions in LIS1 kinetochore function". The Journal of Cell Biology. 156 (6): 959–968. doi:10.1083/jcb.200109046. PMC 2173479. PMID 11889140.
  11. ^ Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI (December 2000). "Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry". The EMBO Journal. 19 (23): 6569–6581. doi:10.1093/emboj/19.23.6569. PMC 305846. PMID 11101529.
  12. ^ a b c d Möller B, Becker LL, Saffari A, Afenjar A, Coci EG, Williamson R, et al. (June 2024). "The expanding clinical and genetic spectrum of DYNC1H1-related disorders". Brain. doi:10.1093/brain/awae183. PMID 38848546.
  13. ^ Marzo MG, Griswold JM, Ruff KM, Buchmeier RE, Fees CP, Markus SM (July 2019). "Molecular basis for dyneinopathies reveals insight into dynein regulation and dysfunction". eLife. 8: e47246. doi:10.7554/eLife.47246. PMC 6733598. PMID 31364990.
  14. ^ "DYNC1H1". ClinVar. U.S. National Library of Medicine. Retrieved 2024-10-03.
  15. ^ Li JT, Dong SQ, Zhu DQ, Yang WB, Qian T, Liu XN, et al. (2022-07-11). "Expanding the Phenotypic and Genetic Spectrum of Neuromuscular Diseases Caused by DYNC1H1 Mutations". Frontiers in Neurology. 13: 943324. doi:10.3389/fneur.2022.943324. PMC 9309508. PMID 35899263.
  16. ^ Cho C, Vale RD (January 2012). "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, et al. (August 2011). "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. 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, et al. (May 2012). "Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy". Neurology. 78 (22): 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, et al. (December 2023). "Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations". bioRxiv. doi:10.1101/2023.11.30.569436. PMC 10705414. PMID 38077003.
  21. ^ Mentis AA, Vlachakis D, Papakonstantinou E, Zaganas I, Patrinos GP, Chrousos GP, et al. (February 2022). "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. doi:10.1101/mcs.a006096. PMC 8958913. PMID 34535505.
  22. ^ a b Cuccurullo C, Cerulli Irelli E, Ugga L, Riva A, D'Amico A, Cabet S, et al. (July 2024). "Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants". Epilepsia. doi:10.1111/epi.18054. PMID 38953796.
  23. ^ Liu W, Cheng M, Zhu Y, Chen Y, Yang Y, Chen H, et al. (April 2023). "DYNC1H1-related epilepsy: Genotype-phenotype correlation". Developmental Medicine and Child Neurology. 65 (4): 534–543. doi:10.1111/dmcn.15414. PMID 36175372.

Further reading

[edit]
[edit]
  • 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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