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{{protein
{{Infobox_gene}}
| Name = desmin
'''Desmin''' is a [[protein]] that in humans is encoded by the ''DES'' [[gene]].<ref name="pmid9736733">{{cite journal | vauthors = Muñoz-Mármol AM, Strasser G, Isamat M, Coulombe PA, Yang Y, Roca X, Vela E, Mate JL, Coll J, Fernández-Figueras MT, Navas-Palacios JJ, Ariza A, Fuchs E | title = A dysfunctional desmin mutation in a patient with severe generalized myopathy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 19 | pages = 11312–7 | date = September 1998 | pmid = 9736733 | pmc = 21639 | doi = 10.1073/pnas.95.19.11312 }}</ref><ref name="pmid2673923">{{cite journal | vauthors = Li ZL, Lilienbaum A, Butler-Browne G, Paulin D | title = Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development | journal = Gene | volume = 78 | issue = 2 | pages = 243–54 | date = May 1989 | pmid = 2673923 | doi = 10.1016/0378-1119(89)90227-8 }}</ref> Desmin is a muscle-specific, type III<ref>[http://www.proteinatlas.org/gene_info.php?ensembl_gene_id=ENSG00000175084&antibody_id=34 The [[Human Protein Atlas]]]. Proteinatlas.org. Retrieved on 2013-07-29.</ref> [[intermediate filament]] that integrates the [[sarcolemma]], [[sarcomere#Bands|Z disk]], and [[nuclear membrane]] in [[sarcomere]]s and regulates sarcomere architecture.<ref>{{cite journal | vauthors = Sequeira V, Nijenkamp LL, Regan JA, van der Velden J | title = The physiological role of cardiac cytoskeleton and its alterations in heart failure | journal = Biochimica et Biophysica Acta | volume = 1838 | issue = 2 | pages = 700–22 | date = February 2014 | pmid = 23860255 | doi = 10.1016/j.bbamem.2013.07.011 }}</ref>
| caption =  
| image =  
| width =  
| HGNCid = 2770
| Symbol = DES
| AltSymbols =  
| EntrezGene = 1674
| OMIM = 125660
| RefSeq = NM_001927
| UniProt = P17661
| PDB =  
| ECnumber =  
| Chromosome = 2
| Arm = q
| Band = 35
| LocusSupplementaryData =  
}}


== Structure ==


'''Desmin''' is a type III [[intermediate filament]] found near the Z line in [[sarcomere]]s. It was first purified in 1977, the [[gene]] was characterized in 1989, and the first knock-out mouse was created in 1996.<ref name="Costa">{{cite journal |last= Costa|first=M. |authorlink= |coauthors=Escaleria, A., Cataldo, A., Oliveria, F., Mermelstein, C. |year=2004 |month=December |quotes=no |title=Desmin: molecular interactions and putative functions of the muscle intermediate filament protein|journal= Brazilian Journal of Medical and Biological Research|volume=37 |issue=12|pages= 1819-1830|issn=0100-879X |url= http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2004001200007|accessdate=2007-03-03 }}</ref> Desmin is only expressed in vertebrates, however homologous proteins are found in many organisms.<ref name="Bar">{{cite journal |last=Bar |first=H |authorlink= |coauthors=Strelkov, S., Sjöberg, G., Aebi, U., and H. Herrmann |year=2004 |month= |title=The biology of desmin filaments: how do mutations affect their structure, assembly, and organization? |journal=Journal of Structural Biology |volume=148 |issue= |pages=137-152 |id= |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WM5-4CC7TCG-1&_user=423519&_coverDate=11%2F30%2F2004&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000020258&_version=1&_urlVersion=0&_userid=423519&md5=74871e00ce96fb7fee379d14683d2f20 |accessdate=2007-03-03 }}</ref> It is a 52kD protein that is a subunit of intermediate filaments in [[skeletal muscle]] tissue, [[smooth muscle]] tissue, and [[cardiac muscle]] tissue.<ref name="Li">{{cite journal |last=Li |first=Z. |authorlink= |coauthors=Agbulut, O., Butler-Browne,G., Carlsson, L., Thornell, L., Babinet, C., and D. Paulin |year=1997 |month= |title=Desmin Is Essential for the Tensile Strength and Integrity of Myofibrils but Not for Myogenic Commitment, Differentiation, and Fusion of Skeletal Muscle |journal=Journal of Cell Biology |volume=139 |issue=1 |pages=129-144 |id= |url=http://www.jcb.org/cgi/content/abstract/139/1/129 |accessdate=2007-03-03 }}</ref>
Desmin is a 53.5 kD protein composed of 470 amino acids.<ref>{{cite web|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P17661 | title =  Mass spectrometry characterization of human DES at COPaKB }}</ref><ref name="Zong_2013">{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref> There are three major domains to the desmin protein: a conserved [[alpha helix]] rod, a variable non alpha helix head, and a carboxy-terminal tail.<ref name="Bar"/> Desmin, as all [[intermediate filaments]], shows no polarity when assembled.<ref name="Bar"/> The rod domain consists of 308 amino acids with parallel alpha helical coiled coil dimers and three linkers to disrupt it.<ref name="Bar"/> The rod domain connects to the head domain. The head domain 84 amino acids with many arginine, serine, and aromatic residues is important in filament assembly and dimer-dimer interactions.<ref name="Bar"/> The tail domain is responsible for the integration of filaments and interaction with proteins and organelles. Desmin is only expressed in vertebrates, however homologous proteins are found in many organisms.<ref name="Bar">{{cite journal | vauthors = Bär H, Strelkov SV, Sjöberg G, Aebi U, Herrmann H | title = The biology of desmin filaments: how do mutations affect their structure, assembly, and organisation? | journal = Journal of Structural Biology | volume = 148 | issue = 2 | pages = 137–52 | date = November 2004 | pmid = 15477095 | doi = 10.1016/j.jsb.2004.04.003 }}</ref> Desmin is a subunit of intermediate filaments in [[cardiac muscle]], [[skeletal muscle]] and [[smooth muscle]] tissue.<ref name="Li">{{cite journal | vauthors = Li Z, Mericskay M, Agbulut O, Butler-Browne G, Carlsson L, Thornell LE, Babinet C, Paulin D | title = Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation, and fusion of skeletal muscle | journal = The Journal of Cell Biology | volume = 139 | issue = 1 | pages = 129–44 | date = October 1997 | pmid = 9314534 | pmc = 2139820 | doi = 10.1083/jcb.139.1.129 }}</ref> In cardiac muscle, desmin is present in [[sarcomere|Z-discs]] and [[intercalated discs]]. Desmin has been shown to [[Protein-protein interaction|interact]] with [[desmoplakin]]<ref name="pmid9261168">{{cite journal | vauthors = Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W | title = Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments | journal = The Journal of Biological Chemistry | volume = 272 | issue = 34 | pages = 21495–503 | date = August 1997 | pmid = 9261168 | doi = 10.1074/jbc.272.34.21495 }}</ref> and [[CRYAB|αB-crystallin]].<ref>{{cite journal | vauthors = Bennardini F, Wrzosek A, Chiesi M | title = Alpha B-crystallin in cardiac tissue. Association with actin and desmin filaments | journal = Circulation Research | volume = 71 | issue = 2 | pages = 288–94 | date = August 1992 | pmid = 1628387 | doi = 10.1161/01.res.71.2.288 }}</ref>


== Suggested Functions==  
== Function ==
The function of desmin has been deduced through studies in knockout mice, however the underlying mechanism of its action is not known. These possibilities may be the result of interactions with other proteins and not desmin itself. More research needs to be done on how desmin's expression and interactions in the muscle cell in order to determine its exact function.


Desmin is one of the earliest protein markers for muscle tissue in embryogenesis as it is detected in the [[somite]]s of [[myoblast]]s.<ref name="Bar"/> Although it is present early in the development of muscle cells it is expressed at low levels and increases as the cell nears terminal differentiation the muscle cell matures only desmin is present. A similar protein, [[vimentin]], is present in higher amounts during embryogenesis while desmin is present in higher amounts after differentiation. This suggests that there may be some interaction between the two in determining muscle cell differentiation. However desmin knockout mice develop normally and only experience defects later in life.<ref name="Li"/> Since desmin is expressed at a low level during differentiation another protein may be able to compensate for desmin's function early in development but not later on.<ref>{{cite web |url=http://www.cbil.upenn.edu/MTIR/dys-toc.html |title=Dystrophin |date=March 16, 1997 |accessdate=2007-04-20}}</ref>  
Desmin was first described in 1976,<ref name="pmid1069986">{{cite journal | vauthors = Lazarides E, Hubbard BD | title = Immunological characterization of the subunit of the 100 A filaments from muscle cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 12 | pages = 4344–8 | date = December 1976 | pmid = 1069986 | pmc = 431448 | doi = 10.1073/pnas.73.12.4344 }}</ref> first purified in 1977,<ref name="pmid266185">{{cite journal | vauthors = Izant JG, Lazarides E | title = Invariance and heterogeneity in the major structural and regulatory proteins of chick muscle cells revealed by two-dimensional gel electrophoresis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 4 | pages = 1450–4 | date = April 1977 | pmid = 266185 | pmc = 430794 | doi = 10.1073/pnas.74.4.1450 }}</ref> the [[gene]] was cloned in 1989,<ref name="pmid2673923"/> and the first [[knockout mouse]] was created in 1996.<ref name="Costa">{{cite journal | vauthors = Costa ML, Escaleira R, Cataldo A, Oliveira F, Mermelstein CS | title = Desmin: molecular interactions and putative functions of the muscle intermediate filament protein | journal = Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas | volume = 37 | issue = 12 | pages = 1819–30 | date = December 2004 | pmid = 15558188 | doi = 10.1590/S0100-879X2004001200007 }}</ref> The function of desmin has been deduced through studies in knockout mice. Desmin is one of the earliest protein markers for muscle tissue in embryogenesis as it is detected in the [[somite]]s.<ref name="Bar"/> Although it is present early in the development of muscle cells, it is only expressed at low levels, and increases as the cell nears terminal differentiation. A similar protein, [[vimentin]], is present in higher amounts during embryogenesis while desmin is present in higher amounts after differentiation. This suggests that there may be some interaction between the two in determining muscle cell differentiation. However desmin knockout mice develop normally and only experience defects later in life.<ref name="Li"/> Since desmin is expressed at a low level during differentiation another protein may be able to compensate for desmin's function early in development but not later on.<ref>{{cite web | url = http://www.cbil.upenn.edu/MTIR/dys-toc.html | title = Dystrophin | date = 1997-03-16 | accessdate=2010-06-28 | work = Catalogue of Regulatory Elements | author = Stoeckert C | publisher = University of Pennsylvania }}</ref>


Desmin is also important in muscle cell architecture and structure since it connects many components of the [[cytoplasm]]. The [[sarcomere]] is a component of muscle cells composed of filaments and [[myosin]] motor proteins which allow the cell to contract. Desmin forms a scaffold around the Z-disk of the sarcomere and connects the Z-disk to the subsarcolemmal cytoskeleton (the cytoplasmic part of the muscle cell plasma membrane).<ref name="Paulin">{{cite journal |last=Paulin |first=D. |authorlink= |coauthors=Li, Z. |year=2004 |month= |title=Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle |journal=Experimental Cell Research |volume=301 |issue=1 |pages=1-7 |id= |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WFC-4D8VGPB-2&_user=423519&_coverDate=11%2F15%2F2004&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000020258&_version=1&_urlVersion=0&_userid=423519&md5=0d8eb44bfdce7294188a25751cc1b8af |accessdate=2007-03-03 }}</ref> It links the [[myofibril]]s laterally by connecting the Z-disks.<ref name="Bar"/> Through its connection to the sarcomere Desmin connects the contractile apparatus to the [[cell nucleus]], [[mitochondria]], and post-synaptic areas of motor endplates.<ref name="Bar"/> These connections maintain the structural and mechanical integrity of the cell during contraction while also helping in force transmission and longitudinal load bearing.<ref name="Paulin"/> <ref name="Shah">{{cite journal |last=Shah |first=S. |authorlink= |coauthors=Davis, J., Weisleder, N., Kostavassili, I., McCulloch, A., Ralston, E., Capetanaki, Y., and R. Lieber |year=2004 |month= |title=Structural and Functional Roles of Desmin in Mouse Skeletal Muscle during Passive Deformation |journal=Biophysical Journal |volume=86 |issue= |pages=2993-3008 |id= |url=http://www.biophysj.org/cgi/content/full/86/5/2993 |accessdate=2007-03-03 }}</ref> There is some evidence that desmin may also connect the sarcomere to the [[extracellular matrix]] (ECM) through desmosomes which could be important in signalling between the ECM and the sarcomere which could regulate muscle contraction and movement.<ref name="Shah"/>
In adult desmin-null mice, hearts from 10 wk-old animals showed drastic alterations in muscle architecture, including a misalignment of myofibrils and disorganization and swelling of mitochondria; findings that were more severe in cardiac relative to skeletal muscle. Cardiac tissue also exhibited progressive necrosis and calcification of the myocardium.<ref>{{cite journal | vauthors = Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y | title = Disruption of muscle architecture and myocardial degeneration in mice lacking desmin | journal = The Journal of Cell Biology | volume = 134 | issue = 5 | pages = 1255–70 | date = September 1996 | pmid = 8794866 | pmc = 2120972 | doi = 10.1083/jcb.134.5.1255 }}</ref> A separate study examined this in more detail in cardiac tissue and found that murine hearts lacking desmin developed [[hypertrophic cardiomyopathy]] and chamber dilation combined with systolic dysfunction.<ref>{{cite journal | vauthors = Milner DJ, Taffet GE, Wang X, Pham T, Tamura T, Hartley C, Gerdes AM, Capetanaki Y | title = The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function | journal = Journal of Molecular and Cellular Cardiology | volume = 31 | issue = 11 | pages = 2063–76 | date = November 1999 | pmid = 10591032 | doi = 10.1006/jmcc.1999.1037 }}</ref> In adult muscle, desmin forms a scaffold around the Z-disk of the sarcomere and connects the Z-disk to the [[sarcolemma|subsarcolemmal]] cytoskeleton.<ref name="Paulin">{{cite journal | vauthors = Paulin D, Li Z | title = Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle | journal = Experimental Cell Research | volume = 301 | issue = 1 | pages = 1–7 | date = November 2004 | pmid = 15501438 | doi = 10.1016/j.yexcr.2004.08.004 }}</ref> It links the [[myofibril]]s laterally by connecting the Z-disks.<ref name="Bar"/> Through its connection to the sarcomere, desmin connects the contractile apparatus to the [[cell nucleus]], [[mitochondria]], and post-synaptic areas of motor endplates.<ref name="Bar"/> These connections maintain the structural and mechanical integrity of the cell during contraction while also helping in force transmission and longitudinal load bearing.<ref name="Paulin"/><ref name="Shah">{{cite journal | vauthors = Shah SB, Davis J, Weisleder N, Kostavassili I, McCulloch AD, Ralston E, Capetanaki Y, Lieber RL | title = Structural and functional roles of desmin in mouse skeletal muscle during passive deformation | journal = Biophysical Journal | volume = 86 | issue = 5 | pages = 2993–3008 | date = May 2004 | pmid = 15111414 | pmc = 1304166 | doi = 10.1016/S0006-3495(04)74349-0 }}</ref>


Finally, desmin may be important in [[mitochondria]] function. When desmin is not functioning properly there is improper mitochondrial distribution, number, morphology and function.<ref name="Goldfarb">{{cite journal |last=Goldfarb |first=L. |authorlink= |coauthors=Vicart, P., Goebel, H., and M. Dalakas |year=2004 |month= |title=Desmin Myopathy |journal=Brain |volume=127 |issue= |pages=723-734 |id= |url=http://brain.oxfordjournals.org/cgi/content/full/127/4/723 |accessdate=2007-03-03 }}</ref> Since desmin links the mitochondria to the sarcomere it may transmit information about contractions and energy need and through this regulate the aerobic respiration rate of the muscle cell.
In human heart failure, desmin expression is upregulated, which has been hyopthesized to be a defense mechanism in an attempt to maintain normal sarcomere alignment amidst disease pathogenesis.<ref>{{cite journal | vauthors = Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, Devaux B, Bauer E, Klövekorn WP, Schlepper M, Schaper W, Schaper J | title = Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium | journal = Circulation Research | volume = 86 | issue = 8 | pages = 846–53 | date = April 2000 | pmid = 10785506 | doi = 10.1161/01.res.86.8.846 }}</ref>  There is some evidence that desmin may also connect the sarcomere to the [[extracellular matrix]] (ECM) through [[desmosomes]] which could be important in signalling between the ECM and the sarcomere which could regulate muscle contraction and movement.<ref name="Shah"/> Finally, desmin may be important in [[mitochondria]] function. When desmin is not functioning properly there is improper mitochondrial distribution, number, morphology and function.<ref name="Milner">{{cite journal | vauthors = Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y | title = Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function. | journal = Journal of Cell Biology | volume = 150 | pages = 1283–1298 | year = 2000 | doi = 10.1083/jcb.150.6.1283 | citeseerx = 10.1.1.273.9903 }}</ref><ref name="Goldfarb">{{cite journal | vauthors = Goldfarb LG, Vicart P, Goebel HH, Dalakas MC | title = Desmin myopathy | journal = Brain | volume = 127 | issue = Pt 4 | pages = 723–34 | date = April 2004 | pmid = 14724127 | doi = 10.1093/brain/awh033 }}</ref> Since desmin links the mitochondria to the sarcomere it may transmit information about contractions and energy need and through this regulate the aerobic respiration rate of the muscle cell.


== Knockout Phenotype ==
== Clinical significance ==


When the gene for desmin is knocked out it is no longer able to function properly. Mice with the desmin knockout gene develop normally and are fertile, however soon after birth they begin to show defects in skeletal, smooth and cardiac muscle; in particular the [[Thoracic diaphragm|diaphragm]] and [[heart]] are affected.<ref name="Li"/> The mice without desmin are weaker and fatigue more easily than wild type mice and the muscle fibers are more likely to be damaged during contraction, presumably because the desmin is responsible for keeping the muslce fibers aligned.<ref name="Li"/> Mice without desmin also have impaired mitochondrial function.
[[Desmin-related myofibrillar myopathy]] (DRM or desminopathy) is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming [[protein filament]]s, and rather, forms aggregates of desmin and other proteins throughout the cell.<ref name="Bar"/> Desmin mutations have been associated with restrictive, dilated <ref>{{cite journal | vauthors = Brodehl A, Dieding M, Biere N, Unger A, Klauke B, Walhorn V, Gummert J, Schulz U, Linke WA, Gerull B, Vorgert M, Anselmetti D, Milting H | title = Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect | journal = Journal of Molecular and Cellular Cardiology | volume = 91 | pages = 207–14 | date = February 2016 | pmid = 26724190 | doi = 10.1016/j.yjmcc.2015.12.015 }}</ref> and idopathic cardiomyopathy.;<ref>{{cite journal|authorlink6=William Zoghbi | vauthors = Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA, Hill R, Bachinski LL, Mann DL, Roberts R | title = Desmin mutation responsible for idiopathic dilated cardiomyopathy | journal = Circulation | volume = 100 | issue = 5 | pages = 461–4 | date = August 1999 | pmid = 10430757 | doi = 10.1161/01.cir.100.5.461 }}</ref><ref>{{cite journal | vauthors = Goldfarb LG, Park KY, Cervenáková L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC | title = Missense mutations in desmin associated with familial cardiac and skeletal myopathy | journal = Nature Genetics | volume = 19 | issue = 4 | pages = 402–3 | date = August 1998 | pmid = 9697706 | doi = 10.1038/1300 }}</ref> and recently, mutations were identified in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).<ref name="pmid20829228">{{cite journal | vauthors = Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H | title = De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy | journal = Human Molecular Genetics | volume = 19 | issue = 23 | pages = 4595–607 | date = December 2010 | pmid = 20829228 | doi = 10.1093/hmg/ddq387 }}</ref><ref>{{cite journal | vauthors = Lorenzon A, Beffagna G, Bauce B, De Bortoli M, Li Mura IE, Calore M, Dazzo E, Basso C, Nava A, Thiene G, Rampazzo A | title = Desmin mutations and arrhythmogenic right ventricular cardiomyopathy | journal = The American Journal of Cardiology | volume = 111 | issue = 3 | pages = 400–5 | date = February 2013 | pmid = 23168288 | pmc = 3554957 | doi = 10.1016/j.amjcard.2012.10.017 }}</ref>  Some of these ''DES'' mutations like p.N116S or p.E114del cause an aggregation of desmin within the [[cytoplasm]].<ref name="pmid22403400">{{cite journal | vauthors = Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Šarić T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H | title = Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants | journal = The Journal of Biological Chemistry | volume = 287 | issue = 19 | pages = 16047–57 | date = May 2012 | pmid = 22403400 | pmc = 3346104 | doi = 10.1074/jbc.M111.313841 }}</ref>
A mutation p.A120D was discovered in a family where several members had sudden cardiac death.<ref name="pmid24200904">{{cite journal | vauthors = Brodehl A, Dieding M, Klauke B, Dec E, Madaan S, Huang T, Gargus J, Fatima A, Saric T, Cakar H, Walhorn V, Tönsing K, Skrzipczyk T, Cebulla R, Gerdes D, Schulz U, Gummert J, Svendsen JH, Olesen MS, Anselmetti D, Christensen AH, Kimonis V, Milting H | title = The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death | journal = Circulation: Cardiovascular Genetics | volume = 6 | issue = 6 | pages = 615–23 | date = December 2013 | pmid = 24200904 | doi = 10.1161/CIRCGENETICS.113.000103 }}</ref>


== Associated Diseases ==
Desmin has been evaluated for role in assessing the depth of invasion of [[urothelial carcinoma]] in [[TURBT]] specimens.<ref>Saha K, Saha A, Datta C, Chatterjee U, Ray S, Bera M. Does desmin immunohistochemistry have a role in assessing stage of urothelial carcinoma in transurethral resection of bladder tumor specimens? Clin Cancer Investig J 2014;3(6):502-7.DOI: 10.4103/2278-0513.142634</ref>
'''Desmin Related Myopathy''' ('''DRM''' or '''Desminopathy''') is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming [[protein filament]]s, instead forming aggregates of desmin and other proteins throughout the cell.<ref name="Bar"/> The sarcomeres become misaligned and result in the disorganization of muscle fibers.<ref name="Bar"/> This mutation also results in muscle cell death by apoptosis and necrosis.<ref name="Bar"/> The muscle cell may also be disorganized because the aggregates may interrupt other filament structures and/or normal cellular function.<ref name="Goldfarb"/> Desminopathies are very rare diseases and only 60 patients have been diagnosed with so far, however this number probably does not accurately represent the population due to frequent mis or under diagnosis.<ref name="Goldfarb"/> Common symptoms of the disease are weakness and atrophy in the distal muscles of the lower limbs which progresses to the hands and arms, then to the trunk, neck and face. Respiratory impairment often follows.
There are three major types of inheritance for this disease: Autosomal dominant, autosomal recessive and de novo. The most severe form is autosomal recessive and it also has the earliest onset.<ref name="Goldfarb"/> It usually involves all three muscle tissues and leads to cardiac and respiratory failure as well as intestinal obstruction.<ref name="Goldfarb"/> Autosomal Dominant inheritance shows a later onset and slower progression. It usually involves only one or two of the muscle tissues.<ref name="Goldfarb"/> De novo diseases occur when a new mutation arises in the person that was not inherited through either parent. This form has a wide range of symptoms and varies depending on the mutation made.<ref name="Goldfarb"/> There is currently no cure for the disease but treatments to help the symptoms are available.<ref name="Goldfarb"/>


== Structure ==
== References ==
There are three major domains to this protein: a conserved [[alpha helix]] rod, a variable non alpha helix head, and a carboxy-terminal tail.<ref name="Bar"/> Desmin, as all [[intermediate filaments]], shows no polarity when assmebled.<ref name="Bar"/> The rod domain consists of 308 amino acids with parallel alpha helical coiled coil dimers and three linkers to disrupt it.<ref name="Bar"/> The rod connects to the head domain. The head domain 84 amino acids with many arginine, serine, and aromatic residues and is important in filament assembly and dimer-dimer interactions.<ref name="Bar"/> The tail domain is responsible for the integration of filaments and interaction with proteins and organelles.
{{reflist|33em}}


==References==
== External links ==
<references/>
* [https://www.ncbi.nlm.nih.gov/books/NBK1499/ GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy]
 
==External links==
* {{MeshName|Desmin}}
* {{MeshName|Desmin}}
[[de:Desmin]]
* [[LOVD]] mutation database: [http://www.dmd.nl/nmdb2/?select_db=DES DES]
[[ja:デスミン]]
 
 


{{Cytoskeletal Proteins}}
{{Cytoskeletal Proteins}}
{{Muscle tissue}}
{{Muscle tissue}}
{{Tumor markers}}


{{WH}}
[[Category:Tumor markers]]
{{WS}}

Latest revision as of 09:44, 17 August 2018

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Desmin is a protein that in humans is encoded by the DES gene.[1][2] Desmin is a muscle-specific, type III[3] intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture.[4]

Structure

Desmin is a 53.5 kD protein composed of 470 amino acids.[5][6] There are three major domains to the desmin protein: a conserved alpha helix rod, a variable non alpha helix head, and a carboxy-terminal tail.[7] Desmin, as all intermediate filaments, shows no polarity when assembled.[7] The rod domain consists of 308 amino acids with parallel alpha helical coiled coil dimers and three linkers to disrupt it.[7] The rod domain connects to the head domain. The head domain 84 amino acids with many arginine, serine, and aromatic residues is important in filament assembly and dimer-dimer interactions.[7] The tail domain is responsible for the integration of filaments and interaction with proteins and organelles. Desmin is only expressed in vertebrates, however homologous proteins are found in many organisms.[7] Desmin is a subunit of intermediate filaments in cardiac muscle, skeletal muscle and smooth muscle tissue.[8] In cardiac muscle, desmin is present in Z-discs and intercalated discs. Desmin has been shown to interact with desmoplakin[9] and αB-crystallin.[10]

Function

Desmin was first described in 1976,[11] first purified in 1977,[12] the gene was cloned in 1989,[2] and the first knockout mouse was created in 1996.[13] The function of desmin has been deduced through studies in knockout mice. Desmin is one of the earliest protein markers for muscle tissue in embryogenesis as it is detected in the somites.[7] Although it is present early in the development of muscle cells, it is only expressed at low levels, and increases as the cell nears terminal differentiation. A similar protein, vimentin, is present in higher amounts during embryogenesis while desmin is present in higher amounts after differentiation. This suggests that there may be some interaction between the two in determining muscle cell differentiation. However desmin knockout mice develop normally and only experience defects later in life.[8] Since desmin is expressed at a low level during differentiation another protein may be able to compensate for desmin's function early in development but not later on.[14]

In adult desmin-null mice, hearts from 10 wk-old animals showed drastic alterations in muscle architecture, including a misalignment of myofibrils and disorganization and swelling of mitochondria; findings that were more severe in cardiac relative to skeletal muscle. Cardiac tissue also exhibited progressive necrosis and calcification of the myocardium.[15] A separate study examined this in more detail in cardiac tissue and found that murine hearts lacking desmin developed hypertrophic cardiomyopathy and chamber dilation combined with systolic dysfunction.[16] In adult muscle, desmin forms a scaffold around the Z-disk of the sarcomere and connects the Z-disk to the subsarcolemmal cytoskeleton.[17] It links the myofibrils laterally by connecting the Z-disks.[7] Through its connection to the sarcomere, desmin connects the contractile apparatus to the cell nucleus, mitochondria, and post-synaptic areas of motor endplates.[7] These connections maintain the structural and mechanical integrity of the cell during contraction while also helping in force transmission and longitudinal load bearing.[17][18]

In human heart failure, desmin expression is upregulated, which has been hyopthesized to be a defense mechanism in an attempt to maintain normal sarcomere alignment amidst disease pathogenesis.[19] There is some evidence that desmin may also connect the sarcomere to the extracellular matrix (ECM) through desmosomes which could be important in signalling between the ECM and the sarcomere which could regulate muscle contraction and movement.[18] Finally, desmin may be important in mitochondria function. When desmin is not functioning properly there is improper mitochondrial distribution, number, morphology and function.[20][21] Since desmin links the mitochondria to the sarcomere it may transmit information about contractions and energy need and through this regulate the aerobic respiration rate of the muscle cell.

Clinical significance

Desmin-related myofibrillar myopathy (DRM or desminopathy) is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming protein filaments, and rather, forms aggregates of desmin and other proteins throughout the cell.[7] Desmin mutations have been associated with restrictive, dilated [22] and idopathic cardiomyopathy.;[23][24] and recently, mutations were identified in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC).[25][26] Some of these DES mutations like p.N116S or p.E114del cause an aggregation of desmin within the cytoplasm.[27] A mutation p.A120D was discovered in a family where several members had sudden cardiac death.[28]

Desmin has been evaluated for role in assessing the depth of invasion of urothelial carcinoma in TURBT specimens.[29]

References

  1. ↑ Muñoz-Mármol AM, Strasser G, Isamat M, Coulombe PA, Yang Y, Roca X, Vela E, Mate JL, Coll J, Fernández-Figueras MT, Navas-Palacios JJ, Ariza A, Fuchs E (September 1998). "A dysfunctional desmin mutation in a patient with severe generalized myopathy". Proceedings of the National Academy of Sciences of the United States of America. 95 (19): 11312–7. doi:10.1073/pnas.95.19.11312. PMC 21639. PMID 9736733.
  2. ↑ 2.0 2.1 Li ZL, Lilienbaum A, Butler-Browne G, Paulin D (May 1989). "Human desmin-coding gene: complete nucleotide sequence, characterization and regulation of expression during myogenesis and development". Gene. 78 (2): 243–54. doi:10.1016/0378-1119(89)90227-8. PMID 2673923.
  3. ↑ The Human Protein Atlas. Proteinatlas.org. Retrieved on 2013-07-29.
  4. ↑ Sequeira V, Nijenkamp LL, Regan JA, van der Velden J (February 2014). "The physiological role of cardiac cytoskeleton and its alterations in heart failure". Biochimica et Biophysica Acta. 1838 (2): 700–22. doi:10.1016/j.bbamem.2013.07.011. PMID 23860255.
  5. ↑ "Mass spectrometry characterization of human DES at COPaKB".
  6. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Bär H, Strelkov SV, Sjöberg G, Aebi U, Herrmann H (November 2004). "The biology of desmin filaments: how do mutations affect their structure, assembly, and organisation?". Journal of Structural Biology. 148 (2): 137–52. doi:10.1016/j.jsb.2004.04.003. PMID 15477095.
  8. ↑ 8.0 8.1 Li Z, Mericskay M, Agbulut O, Butler-Browne G, Carlsson L, Thornell LE, Babinet C, Paulin D (October 1997). "Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation, and fusion of skeletal muscle". The Journal of Cell Biology. 139 (1): 129–44. doi:10.1083/jcb.139.1.129. PMC 2139820. PMID 9314534.
  9. ↑ Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W (August 1997). "Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments". The Journal of Biological Chemistry. 272 (34): 21495–503. doi:10.1074/jbc.272.34.21495. PMID 9261168.
  10. ↑ Bennardini F, Wrzosek A, Chiesi M (August 1992). "Alpha B-crystallin in cardiac tissue. Association with actin and desmin filaments". Circulation Research. 71 (2): 288–94. doi:10.1161/01.res.71.2.288. PMID 1628387.
  11. ↑ Lazarides E, Hubbard BD (December 1976). "Immunological characterization of the subunit of the 100 A filaments from muscle cells". Proceedings of the National Academy of Sciences of the United States of America. 73 (12): 4344–8. doi:10.1073/pnas.73.12.4344. PMC 431448. PMID 1069986.
  12. ↑ Izant JG, Lazarides E (April 1977). "Invariance and heterogeneity in the major structural and regulatory proteins of chick muscle cells revealed by two-dimensional gel electrophoresis". Proceedings of the National Academy of Sciences of the United States of America. 74 (4): 1450–4. doi:10.1073/pnas.74.4.1450. PMC 430794. PMID 266185.
  13. ↑ Costa ML, Escaleira R, Cataldo A, Oliveira F, Mermelstein CS (December 2004). "Desmin: molecular interactions and putative functions of the muscle intermediate filament protein". Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Medicas E Biologicas. 37 (12): 1819–30. doi:10.1590/S0100-879X2004001200007. PMID 15558188.
  14. ↑ Stoeckert C (1997-03-16). "Dystrophin". Catalogue of Regulatory Elements. University of Pennsylvania. Retrieved 2010-06-28.
  15. ↑ Milner DJ, Weitzer G, Tran D, Bradley A, Capetanaki Y (September 1996). "Disruption of muscle architecture and myocardial degeneration in mice lacking desmin". The Journal of Cell Biology. 134 (5): 1255–70. doi:10.1083/jcb.134.5.1255. PMC 2120972. PMID 8794866.
  16. ↑ Milner DJ, Taffet GE, Wang X, Pham T, Tamura T, Hartley C, Gerdes AM, Capetanaki Y (November 1999). "The absence of desmin leads to cardiomyocyte hypertrophy and cardiac dilation with compromised systolic function". Journal of Molecular and Cellular Cardiology. 31 (11): 2063–76. doi:10.1006/jmcc.1999.1037. PMID 10591032.
  17. ↑ 17.0 17.1 Paulin D, Li Z (November 2004). "Desmin: a major intermediate filament protein essential for the structural integrity and function of muscle". Experimental Cell Research. 301 (1): 1–7. doi:10.1016/j.yexcr.2004.08.004. PMID 15501438.
  18. ↑ 18.0 18.1 Shah SB, Davis J, Weisleder N, Kostavassili I, McCulloch AD, Ralston E, Capetanaki Y, Lieber RL (May 2004). "Structural and functional roles of desmin in mouse skeletal muscle during passive deformation". Biophysical Journal. 86 (5): 2993–3008. doi:10.1016/S0006-3495(04)74349-0. PMC 1304166. PMID 15111414.
  19. ↑ Heling A, Zimmermann R, Kostin S, Maeno Y, Hein S, Devaux B, Bauer E, Klövekorn WP, Schlepper M, Schaper W, Schaper J (April 2000). "Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium". Circulation Research. 86 (8): 846–53. doi:10.1161/01.res.86.8.846. PMID 10785506.
  20. ↑ Milner DJ, Mavroidis M, Weisleder N, Capetanaki Y (2000). "Desmin cytoskeleton linked to muscle mitochondrial distribution and respiratory function". Journal of Cell Biology. 150: 1283–1298. CiteSeerX 10.1.1.273.9903. doi:10.1083/jcb.150.6.1283.
  21. ↑ Goldfarb LG, Vicart P, Goebel HH, Dalakas MC (April 2004). "Desmin myopathy". Brain. 127 (Pt 4): 723–34. doi:10.1093/brain/awh033. PMID 14724127.
  22. ↑ Brodehl A, Dieding M, Biere N, Unger A, Klauke B, Walhorn V, Gummert J, Schulz U, Linke WA, Gerull B, Vorgert M, Anselmetti D, Milting H (February 2016). "Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect". Journal of Molecular and Cellular Cardiology. 91: 207–14. doi:10.1016/j.yjmcc.2015.12.015. PMID 26724190.
  23. ↑ Li D, Tapscoft T, Gonzalez O, Burch PE, Quiñones MA, Zoghbi WA, Hill R, Bachinski LL, Mann DL, Roberts R (August 1999). "Desmin mutation responsible for idiopathic dilated cardiomyopathy". Circulation. 100 (5): 461–4. doi:10.1161/01.cir.100.5.461. PMID 10430757.
  24. ↑ Goldfarb LG, Park KY, Cervenáková L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC (August 1998). "Missense mutations in desmin associated with familial cardiac and skeletal myopathy". Nature Genetics. 19 (4): 402–3. doi:10.1038/1300. PMID 9697706.
  25. ↑ Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H (December 2010). "De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy". Human Molecular Genetics. 19 (23): 4595–607. doi:10.1093/hmg/ddq387. PMID 20829228.
  26. ↑ Lorenzon A, Beffagna G, Bauce B, De Bortoli M, Li Mura IE, Calore M, Dazzo E, Basso C, Nava A, Thiene G, Rampazzo A (February 2013). "Desmin mutations and arrhythmogenic right ventricular cardiomyopathy". The American Journal of Cardiology. 111 (3): 400–5. doi:10.1016/j.amjcard.2012.10.017. PMC 3554957. PMID 23168288.
  27. ↑ Brodehl A, Hedde PN, Dieding M, Fatima A, Walhorn V, Gayda S, Šarić T, Klauke B, Gummert J, Anselmetti D, Heilemann M, Nienhaus GU, Milting H (May 2012). "Dual color photoactivation localization microscopy of cardiomyopathy-associated desmin mutants". The Journal of Biological Chemistry. 287 (19): 16047–57. doi:10.1074/jbc.M111.313841. PMC 3346104. PMID 22403400.
  28. ↑ Brodehl A, Dieding M, Klauke B, Dec E, Madaan S, Huang T, Gargus J, Fatima A, Saric T, Cakar H, Walhorn V, Tönsing K, Skrzipczyk T, Cebulla R, Gerdes D, Schulz U, Gummert J, Svendsen JH, Olesen MS, Anselmetti D, Christensen AH, Kimonis V, Milting H (December 2013). "The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death". Circulation: Cardiovascular Genetics. 6 (6): 615–23. doi:10.1161/CIRCGENETICS.113.000103. PMID 24200904.
  29. ↑ Saha K, Saha A, Datta C, Chatterjee U, Ray S, Bera M. Does desmin immunohistochemistry have a role in assessing stage of urothelial carcinoma in transurethral resection of bladder tumor specimens? Clin Cancer Investig J 2014;3(6):502-7.DOI: 10.4103/2278-0513.142634

External links

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