Distrofin

DMD
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1DXX, 1EG3, 1EG4, 3UUN
Identifikatori
Aliasi	DMD
Vanjski ID-jevi	OMIM: 300377 MGI: 94909 HomoloGene: 20856 GeneCards: DMD
Lokacija gena (čovjek)
Hrom.	Hromosom X
Kraj	33,339,609 bp
Lokacija gena (miš)
Hrom.	Hromosom X (miš)
Kraj	84,249,747 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• nitric-oxide synthase binding; • dystroglycan binding; • vinculin binding; • myosin binding; • vezivanje iona cinka; • vezivanje iona metala; • GO:0001948, GO:0016582 vezivanje za proteine; • actin binding; • structural constituent of muscle; • structural constituent of cytoskeleton;
Ćelijska komponenta	• citoplazma; • citosol; • postsynaptic membrane; • lateral plasma membrane; • membrana; • Filopodija; • cell-substrate junction; • ćelijska membrana; • sinapsa; • dystrophin-associated glycoprotein complex; • cell surface; • međućelijske veze; • Z discdkac; • actin cytoskeleton; • Lipidni splav; • Sarkolema; • Kostamera; • syntrophin complex; • neuron projection terminus; • citoskelet; • jedro; • filopodium membrane; • GO:0009327 makromolekulani kompleks;
Biološki proces	• response to muscle stretch; • regulation of ryanodine-sensitive calcium-release channel activity; • cardiac muscle cell action potential; • regulation of voltage-gated calcium channel activity; • cardiac muscle contraction; • muscle cell cellular homeostasis; • negative regulation of peptidyl-cysteine S-nitrosylation; • regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion; • peptide biosynthetic process; • muscle organ development; • regulation of heart rate; • positive regulation of neuron differentiation; • negative regulation of peptidyl-serine phosphorylation; • positive regulation of neuron projection development; • muscle filament sliding; • positive regulation of sodium ion transmembrane transporter activity; • regulation of cellular response to growth factor stimulus; • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; • motile cilium assembly; • regulation of skeletal muscle contraction; • regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion; • cytoskeleton organization;
	Izvori:Amigo / QuickGO
Ortolozi
	1756
	13405
	ENSG00000198947
	ENSMUSG00000045103
	P11532
	P11531
NM_000109; NM_004006; NM_004007; NM_004009; NM_004010;
	NM_004011; NM_004012; NM_004013; NM_004014; NM_004015; NM_004016; NM_004017; NM_004018; NM_004019; NM_004020; NM_004021; NM_004022; NM_004023
NM_007868; NM_001314034; NM_001314035; NM_001314036; NM_001314037;
	NM_001314038
NP_000100; NP_003997; NP_004000; NP_004001; NP_004002;
	NP_004003; NP_004004; NP_004005; NP_004006; NP_004007; NP_004008; NP_004009; NP_004010; NP_004011; NP_004012; NP_004013; NP_004014
NP_001300963; NP_001300964; NP_001300965; NP_001300966; NP_001300967;
	NP_031894
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Distrofin je štapičasti citoplazmatski protein i vitalni dio proteinskog kompleksa koji povezuje citoskelet mišićnih vlakana do okolnog vanćelijskog matriksa kroz ćelijsku membranu. Ovaj kompleks je poznat pod različitim nazivima, kao kostamera ili distrofin-vezani proteinski kompleks (DAPC). Na kostameri sa distrofinom kolokalizuju se mnogi mišićni proteini, kao što su α-distrobrevin, sinkoilin, sinemin, sarkoglikan, distroglikan i sarkospan.

Gen DMD, koji kodira protein distrofin, jedan je od najdužih poznatih ljudskih gena, pokrivajući 2,3 megabaza (0,08% ljudskog genoma) na lokusu Xp21. Primarni transkript u mišiću iznosi oko 2100 kilobaza i treba mu 16 sati da se transkribira;^[5] zrela iRNK ima 14,0 kilobaza.^[6] Transkript od 79 mišićnih egzona^[7] kodira protein od 3.685 aminokiselinskih ostataka.^[8]

Funkcija

Distrofin je protein smješten između sarkoleme i najudaljenijeg sloja miofilamenta u mišićnom vlaknu (miofibrila). To je kohezivni protein koji povezuje aktinske filamente s drugim potpornim proteinima koji se nalaze na unutrašnjoj površini plazmatske membrane svakog mišićnog vlakna (sarkoleme). Ovi potporni proteini na unutrašnjoj površini sarkoleme zauzvrat se povezuju s dva druga uzastopna proteina, što ukupno daje tri vezana proteina. Konačni vezni protein vezan je za vlaknasti endomizij cijelog mišićnog vlakna. Distrofin podržava snagu mišićnih vlakana, a njegovo odsustvo smanjuje kontrakcije mišića, povećava sarkolemnu deformabilnost i ugrožava mehaničku stabilnost kostamera i njihovih veza sa obližnjim miofibrilima. To se pokazalo u nedavnim studijama, u kojima su izmjerena biomehanička svojstva sarkoleme i njene veze, preko kostamera sa kontraktilnim aparatom,^[9] i pomaže u sprečavanju ozljeda mišićnih vlakana. Pokret tankih filamenata (aktin) stvara vučnu silu na vanćelijskom vezivnom tkivu, koje na kraju postaje tetiva mišića. Proteinski kompleks povezan sa distrofinom također pomaže skaliranje različitih signalnik i kanalnih proteina, što implicira DAPC u regulaciji signalnih procesa.^[10]

Patologija

Nedostatak distrofina definitivno je utvrđen kao jedan od osnovnih uzroka opće klase miopatije zajednički zvane mišićna distrofija. Delecije jednog ili nekoliko egzona gena za distrofin DMD uzrokuju Duchenneovu i Beckerovu mišićnu distrofiju.^[11] Veliki citosolni protein prvi je identificirao Louis M. Kunkel 1987.,^[12] nakon istovremenih radova Kunkela i Roberta G. Wortona u karakterizirajnu mutiranog gena koji uzrokuje Duchenovu mišićnu distrofiju (DMD).^[13]^[14]

Normalno tkivo skeletnih mišića sadrži samo male količine distrofina (oko 0,002% ukupnih mišićnih proteina),^[12] ali njegovo odsustvo (ili abnormalno izražavanje) dovodi do razvoja teške i danas neizlječive konstelacije simptoma koju najlakše karakterizira nekoliko aberantnih unutarćelijskih signalnih puteva, koji u konačnici izazivaju izraženu miofibrilnu nekrozu, kao i progresivnu mišićnu slabost i umor. Većina bolesnika s DMD-om rano u životu postaje ovisna o invalidskim kolicima, a postepeni razvoj hipertrofije srca – posljedica teške fibroze miokarda – obično rezultira preranom smrću, u prve dvije ili tri decenije života. Varijante (mutacije) u genu DMD koje dovode do stvaranja premalo ili oštećenog, interno skraćenog, ali djelomično funkcionalnog distrofina, rezultiraju mnogo blažim distrofijskim fenotipom u pogođenih pacijenata, što rezultira bolešću poznatom kao Beckerova mišićna distrofija (BMD). U nekim slučajevima fenotip pacijenta je takav da stručnjaci mogu različito odlučiti treba li pacijentu dijagnosticirati DMD ili BMD.

Pravilo okvira čitanja je teorija koja se danas najčešće koristi za predviđanje hoće li neka varijanta rezultirati fenotipom DMD ili BMD.^[15]

Iako njegova uloga u glatkim mišićima dišnih puteva nije dobro utvrđena, nedavna istraživanja pokazuju da je distrofin zajedno sa ostalim podjedinicama distrofinskog glikoproteinskog kompleksa povezan sa sazrijevanjem fenotipa.^[16]

Interakcije

Pokazano je da distrofin učestvuje u interakcijama sa:

Neandertalska primjesa

Izgleda da se varijanta gena DMD, koja se nalazi na hromosomu X, zvana B006, pojavila introgresijom, nakon parenja neandertalaca i modernih ljudi.^[22]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000198947 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000045103 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Tennyson CN, Klamut HJ, Worton RG (februar 1995). "The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced". Nature Genetics. 9 (2): 184–90. doi:10.1038/ng0295-184. PMID 7719347.
^ NCBI Sequence Viewer v2.0
^ Strachan T and Read AP, 1999. Human molecular genetics, BIOS Scientific, New York, USA
^ NCBI Sequence Viewer v2.0
^ García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (mart 2011). "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice". Journal of Muscle Research and Cell Motility. 31 (5–6): 323–36. doi:10.1007/s10974-011-9238-9. PMC 4326082. PMID 21312057.
^ Constantin B (februar 2014). "Dystrophin complex functions as a scaffold for signalling proteins". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1838 (2): 635–42. doi:10.1016/j.bbamem.2013.08.023. PMID 24021238.
^ Le Rumeur E. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies. Bosn J of Basic Med Sci. 2015;15(3):14-0. Bosn J of Basic Med Sci. DOI: https://doi.org/10.17305/bjbms.2015.636 PMCID: PMC4594321 PMID 26295289
^ ^a ^b Hoffman EP, Brown RH, Kunkel LM (decembar 1987). "Dystrophin: the protein product of the Duchenne muscular dystrophy locus". Cell. 51 (6): 919–28. doi:10.1016/0092-8674(87)90579-4. PMID 3319190.
^ Monaco AP, Neve RL, Colletti-Feener C, Bertelson CJ, Kurnit DM, Kunkel LM (1986). "Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene". Nature. 323 (6089): 646–50. Bibcode:1986Natur.323..646M. doi:10.1038/323646a0. PMID 3773991.
^ Burghes AH, Logan C, Hu X, Belfall B, Worton RG, Ray PN (1987). "A cDNA clone from the Duchenne/Becker muscular dystrophy gene". Nature. 328 (6129): 434–7. doi:10.1038/328434a0. PMID 3614347.
^ Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT (august 2006). "Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule". Muscle & Nerve. 34 (2): 135–44. doi:10.1002/mus.20586. PMID 16770791.
^ Sharma P, Tran T, Stelmack GL, McNeill K, Gosens R, Mutawe MM, Unruh H, Gerthoffer WT, Halayko AJ (januar 2008). "Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation". American Journal of Physiology. Lung Cellular and Molecular Physiology. 294 (1): L57–68. doi:10.1152/ajplung.00378.2007. PMID 17993586.
^ Sadoulet-Puccio HM, Rajala M, Kunkel LM (novembar 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12413–8. Bibcode:1997PNAS...9412413S. doi:10.1073/pnas.94.23.12413. PMC 24974. PMID 9356463.
^ Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM (februar 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". The Journal of Biological Chemistry. 271 (5): 2724–30. doi:10.1074/jbc.271.5.2724. PMID 8576247.
^ Yang B, Jung D, Rafael JA, Chamberlain JS, Campbell KP (mart 1995). "Identification of alpha-syntrophin binding to syntrophin triplet, dystrophin, and utrophin". The Journal of Biological Chemistry. 270 (10): 4975–8. doi:10.1074/jbc.270.10.4975. PMID 7890602.
^ Gee SH, Madhavan R, Levinson SR, Caldwell JH, Sealock R, Froehner SC (januar 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". The Journal of Neuroscience. 18 (1): 128–37. doi:10.1523/jneurosci.18-01-00128.1998. PMC 6793384. PMID 9412493.
^ Ahn AH, Kunkel LM (februar 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". The Journal of Cell Biology. 128 (3): 363–71. doi:10.1083/jcb.128.3.363. PMC 2120343. PMID 7844150.
^ Khan R (25. 1. 2011). "Neandertal admixture, revisiting results after shaken priors". Discover Magazine. Arhivirano s originala, 27. 1. 2013. Pristupljeno 27. 3. 2013.

Dopunska literatura

Roberts RG, Gardner RJ, Bobrow M (1994). "Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations". Human Mutation. 4 (1): 1–11. doi:10.1002/humu.1380040102. PMID 7951253.
Tinsley JM, Blake DJ, Zuellig RA, Davies KE (august 1994). "Increasing complexity of the dystrophin-associated protein complex". Proceedings of the National Academy of Sciences of the United States of America. 91 (18): 8307–13. Bibcode:1994PNAS...91.8307T. doi:10.1073/pnas.91.18.8307. PMC 44595. PMID 8078878.
Blake DJ, Weir A, Newey SE, Davies KE (april 2002). "Function and genetics of dystrophin and dystrophin-related proteins in muscle". Physiological Reviews. 82 (2): 291–329. doi:10.1152/physrev.00028.2001. PMID 11917091. Arhivirano s originala, 2. 12. 2017. Pristupljeno 4. 3. 2021.
Röper K, Gregory SL, Brown NH (novembar 2002). "The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families". Journal of Cell Science. 115 (Pt 22): 4215–25. doi:10.1242/jcs.00157. PMID 12376554.
Muntoni F, Torelli S, Ferlini A (decembar 2003). "Dystrophin and mutations: one gene, several proteins, multiple phenotypes". The Lancet. Neurology. 2 (12): 731–40. doi:10.1016/S1474-4422(03)00585-4. PMID 14636778.
Haenggi T, Fritschy JM (juli 2006). "Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue" (PDF). Cellular and Molecular Life Sciences. 63 (14): 1614–31. doi:10.1007/s00018-005-5461-0. PMID 16710609.

Commons logo

Commons ima datoteke na temu: Distrofin

Vanjski linkovi

GeneReviews/NCBI/NIH/UW entry on Dystrophinopathies
Dystrophin na US National Library of Medicine Medical Subject Headings (MeSH)
LOVD mutation database: DMD, DMD (whole exon changes)

Vanjski linkovi

LOVD mutation database: SGCB

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000198947 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000045103 - Ensembl, maj 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] Tennyson CN, Klamut HJ, Worton RG (februar 1995). "The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced". Nature Genetics. 9 (2): 184–90. doi:10.1038/ng0295-184. PMID 7719347.

[6] NCBI Sequence Viewer v2.0

[7] Strachan T and Read AP, 1999. Human molecular genetics, BIOS Scientific, New York, USA

[8] NCBI Sequence Viewer v2.0

[9] García-Pelagio KP, Bloch RJ, Ortega A, González-Serratos H (mart 2011). "Biomechanics of the sarcolemma and costameres in single skeletal muscle fibers from normal and dystrophin-null mice". Journal of Muscle Research and Cell Motility. 31 (5–6): 323–36. doi:10.1007/s10974-011-9238-9. PMC 4326082. PMID 21312057.

[10] Constantin B (februar 2014). "Dystrophin complex functions as a scaffold for signalling proteins". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1838 (2): 635–42. doi:10.1016/j.bbamem.2013.08.023. PMID 24021238.

[11] Le Rumeur E. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies. Bosn J of Basic Med Sci. 2015;15(3):14-0. Bosn J of Basic Med Sci. DOI: https://doi.org/10.17305/bjbms.2015.636 PMCID: PMC4594321 PMID 26295289

[Dystrophin:_the_protein_product_of-12] Hoffman EP, Brown RH, Kunkel LM (decembar 1987). "Dystrophin: the protein product of the Duchenne muscular dystrophy locus". Cell. 51 (6): 919–28. doi:10.1016/0092-8674(87)90579-4. PMID 3319190.

[13] Monaco AP, Neve RL, Colletti-Feener C, Bertelson CJ, Kurnit DM, Kunkel LM (1986). "Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene". Nature. 323 (6089): 646–50. Bibcode:1986Natur.323..646M. doi:10.1038/323646a0. PMID 3773991.

[pmid3614347-14] Burghes AH, Logan C, Hu X, Belfall B, Worton RG, Ray PN (1987). "A cDNA clone from the Duchenne/Becker muscular dystrophy gene". Nature. 328 (6129): 434–7. doi:10.1038/328434a0. PMID 3614347.

[15] Aartsma-Rus A, Van Deutekom JC, Fokkema IF, Van Ommen GJ, Den Dunnen JT (august 2006). "Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule". Muscle & Nerve. 34 (2): 135–44. doi:10.1002/mus.20586. PMID 16770791.

[16] Sharma P, Tran T, Stelmack GL, McNeill K, Gosens R, Mutawe MM, Unruh H, Gerthoffer WT, Halayko AJ (januar 2008). "Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation". American Journal of Physiology. Lung Cellular and Molecular Physiology. 294 (1): L57–68. doi:10.1152/ajplung.00378.2007. PMID 17993586.

[pmid9356463-17] Sadoulet-Puccio HM, Rajala M, Kunkel LM (novembar 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12413–8. Bibcode:1997PNAS...9412413S. doi:10.1073/pnas.94.23.12413. PMC 24974. PMID 9356463.

[pmid8576247-18] Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM (februar 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". The Journal of Biological Chemistry. 271 (5): 2724–30. doi:10.1074/jbc.271.5.2724. PMID 8576247.

[pmid7890602-19] Yang B, Jung D, Rafael JA, Chamberlain JS, Campbell KP (mart 1995). "Identification of alpha-syntrophin binding to syntrophin triplet, dystrophin, and utrophin". The Journal of Biological Chemistry. 270 (10): 4975–8. doi:10.1074/jbc.270.10.4975. PMID 7890602.

[pmid9412493-20] Gee SH, Madhavan R, Levinson SR, Caldwell JH, Sealock R, Froehner SC (januar 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". The Journal of Neuroscience. 18 (1): 128–37. doi:10.1523/jneurosci.18-01-00128.1998. PMC 6793384. PMID 9412493.

[pmid7844150-21] Ahn AH, Kunkel LM (februar 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". The Journal of Cell Biology. 128 (3): 363–71. doi:10.1083/jcb.128.3.363. PMC 2120343. PMID 7844150.

[22] Khan R (25. 1. 2011). "Neandertal admixture, revisiting results after shaken priors". Discover Magazine. Arhivirano s originala, 27. 1. 2013. Pristupljeno 27. 3. 2013.

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