View source for CSRP3

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{{Short description|Protein-coding gene in humans}}
{{Infobox_gene}}
'''Cysteine and glycine-rich protein 3''' also known as '''cardiac LIM protein''' (CLP) or '''muscle LIM protein''' (MLP) is a [[protein]] that in humans is encoded by the '''CSRP3''' [[gene]].<ref name=a3>{{cite journal | vauthors = Arber S, Halder G, Caroni P | title = Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation | journal = Cell | volume = 79 | issue = 2 | pages = 221–31 | date = October 1994 | pmid = 7954791 | doi = 10.1016/0092-8674(94)90192-9 | s2cid = 26650433 }}</ref>

CSRP3 IS a small 194 amino acid protein, which is specifically expressed in [[skeletal muscle|skeletal]] and [[cardiac muscle]].<ref name=a1>{{cite journal | vauthors = Gehmlich K, Geier C, Milting H, Fürst D, Ehler E | title = Back to square one: what do we know about the functions of muscle LIM protein in the heart? | journal = Journal of Muscle Research and Cell Motility | volume = 29 | issue = 6–8 | pages = 155–8 | date = 2008 | pmid = 19115046 | doi = 10.1007/s10974-008-9159-4 | s2cid = 9251900 }}</ref><ref name=a2>{{cite journal | vauthors = Knöll R, Hoshijima M, Chien KR | title = Muscle LIM protein in heart failure | journal = Experimental and Clinical Cardiology | volume = 7 | issue = 2–3 | pages = 104–5 | date = 2001 | pmid = 19649232 | pmc = 2719181 }}</ref> In rodents, CSRP3 has also been found to be expressed in [[neuron]]s.<ref name = "Levin_2019">{{cite journal | vauthors = Levin E, Leibinger M, Gobrecht P, Hilla A, Andreadaki A, Fischer D | title = Muscle LIM Protein Is Expressed in the Injured Adult CNS and Promotes Axon Regeneration | language = English | journal = Cell Reports | volume = 26 | issue = 4 | pages = 1021–1032.e6 | date = January 2019 | pmid = 30673598 | doi = 10.1016/j.celrep.2018.12.026 | doi-access = free }}</ref>

== Gene ==
The CSRP3 gene was discovered in rat in 1994.<ref name=a3/> In humans it was mapped to [[chromosome 11]]p15.1,<ref name=a4>{{cite journal | vauthors = Fung YW, Wang R, Liew CC | title = Characterization of a human cardiac gene which encodes for a LIM domain protein and is developmentally expressed in myocardial development | journal = Journal of Molecular and Cellular Cardiology | volume = 28 | issue = 6 | pages = 1203–10 | date = June 1996 | pmid = 8782062 | doi = 10.1006/jmcc.1996.0111 }}</ref><ref name=a5>{{cite journal | vauthors = Fung YW, Wang RX, Heng HH, Liew CC | title = Mapping of a human LIM protein (CLP) to human chromosome 11p15.1 by fluorescence in situ hybridization | journal = Genomics | volume = 28 | issue = 3 | pages = 602–3 | date = August 1995 | pmid = 7490106 | doi = 10.1006/geno.1995.1200 }}</ref> where it spans a 20kb genomic region, organized in 6 [[exons]]. The full length transcript is 0.8kb,<ref name=a4/><ref name=a6>{{cite journal | vauthors = Knöll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR | title = The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy | journal = Cell | volume = 111 | issue = 7 | pages = 943–55 | date = December 2002 | pmid = 12507422 | doi = 10.1016/s0092-8674(02)01226-6 | s2cid = 15082967 | doi-access = free }}</ref> while a splice variant, originating from the [[alternative splicing]] of exons 3 and 4, was recently identified and designated MLP-b.<ref name=a7>{{cite journal | vauthors = Vafiadaki E, Arvanitis DA, Papalouka V, Terzis G, Roumeliotis TI, Spengos K, Garbis SD, Manta P, Kranias EG, Sanoudou D | title = Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation | journal = The FEBS Journal | volume = 281 | issue = 14 | pages = 3261–79 | date = July 2014 | pmid = 24860983 | pmc = 4416226 | doi = 10.1111/febs.12859 }}</ref>

== Structure ==
MLP contains two [[LIM domain]]s (LIM1 and LIM2), each being surrounded by glycine-rich regions, and the two separated by more than 50 residues.<ref name=a8>{{cite journal | vauthors = Weiskirchen R, Pino JD, Macalma T, Bister K, Beckerle MC | title = The cysteine-rich protein family of highly related LIM domain proteins | journal = The Journal of Biological Chemistry | volume = 270 | issue = 48 | pages = 28946–54 | date = December 1995 | pmid = 7499425 | doi = 10.1074/jbc.270.48.28946 | doi-access = free }}</ref> LIM domains offer a remarkable ability for [[protein-protein interactions]].<ref name=a9>{{cite journal | vauthors = Buyandelger B, Ng KE, Miocic S, Piotrowska I, Gunkel S, Ku CH, Knöll R | title = MLP (muscle LIM protein) as a stress sensor in the heart | journal = Pflügers Archiv | volume = 462 | issue = 1 | pages = 135–42 | date = July 2011 | pmid = 21484537 | pmc = 3114083 | doi = 10.1007/s00424-011-0961-2 }}</ref> Furthermore, MLP carries a [[nuclear localization signal]] at [[amino acid]] positions 64-69 <ref name=a10>{{cite journal | vauthors = Bos JM, Poley RN, Ny M, Tester DJ, Xu X, Vatta M, Towbin JA, Gersh BJ, Ommen SR, Ackerman MJ | title = Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin | journal = Molecular Genetics and Metabolism | volume = 88 | issue = 1 | pages = 78–85 | date = May 2006 | pmid = 16352453 | pmc = 2756511 | doi = 10.1016/j.ymgme.2005.10.008 }}</ref> MLP can be acetylated/deacetylated at the position 69 lysine residue (K69), by [[acetyltransferase]] (PCAF) and  histone deacetylase 4 ([[HDAC4]]), respectively.<ref name=a11>{{cite journal | vauthors = Gupta MP, Samant SA, Smith SH, Shroff SG | title = HDAC4 and PCAF bind to cardiac sarcomeres and play a role in regulating myofilament contractile activity | journal = The Journal of Biological Chemistry | volume = 283 | issue = 15 | pages = 10135–46 | date = April 2008 | pmid = 18250163 | pmc = 2442284 | doi = 10.1074/jbc.M710277200 | doi-access = free }}</ref> In [[myocytes]], MLP has the ability to [[oligomerize]], forming dimers, trimers and tetramers, an attribute that impacts its interactions, localization and function.<ref name=a12>{{cite journal | vauthors = Boateng SY, Belin RJ, Geenen DL, Margulies KB, Martin JL, Hoshijima M, de Tombe PP, Russell B | s2cid = 9591608 | title = Cardiac dysfunction and heart failure are associated with abnormalities in the subcellular distribution and amounts of oligomeric muscle LIM protein | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 292 | issue = 1 | pages = H259–69 | date = January 2007 | pmid = 16963613 | doi = 10.1152/ajpheart.00766.2006 }}</ref>

== Protein interactions and localization ==
MLP has been identified to bind to an increasing list of proteins, exhibiting variable subcellular localization and diverse functional properties. In particular, MLP interacts with proteins at the: 
# [[Sarcomere|Z-line]], including [[telethonin]] (T-cap), alpha-[[actinin]] ([[ACTN]]), [[cofilin]]-2 ([[CFL2 (gene)|CFL2]]), [[calcineurin]], [[HDAC4]], MLP-b as well as to MLP itself;<ref name=a6/><ref name=a7/><ref name=a11/><ref name=a13>{{cite journal | vauthors = Louis HA, Pino JD, Schmeichel KL, Pomiès P, Beckerle MC | title = Comparison of three members of the cysteine-rich protein family reveals functional conservation and divergent patterns of gene expression | journal = The Journal of Biological Chemistry | volume = 272 | issue = 43 | pages = 27484–91 | date = October 1997 | pmid = 9341203 | doi = 10.1074/jbc.272.43.27484 | doi-access =  free}}</ref><ref name=a14>{{cite journal | vauthors = Papalouka V, Arvanitis DA, Vafiadaki E, Mavroidis M, Papadodima SA, Spiliopoulou CA, Kremastinos DT, Kranias EG, Sanoudou D | title = Muscle LIM protein interacts with cofilin 2 and regulates F-actin dynamics in cardiac and skeletal muscle | journal = Molecular and Cellular Biology | volume = 29 | issue = 22 | pages = 6046–58 | date = November 2009 | pmid = 19752190 | pmc = 2772566 | doi = 10.1128/MCB.00654-09 }}</ref><ref name=a15>{{cite journal | vauthors = Zolk O, Caroni P, Böhm M | title = Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure | journal = Circulation | volume = 101 | issue = 23 | pages = 2674–7 | date = June 2000 | pmid = 10851202 | doi = 10.1161/01.cir.101.23.2674 | doi-access = free }}</ref><ref name=a16>{{cite journal | vauthors = Heineke J, Ruetten H, Willenbockel C, Gross SC, Naguib M, Schaefer A, Kempf T, Hilfiker-Kleiner D, Caroni P, Kraft T, Kaiser RA, Molkentin JD, Drexler H, Wollert KC | title = Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 5 | pages = 1655–60 | date = February 2005 | pmid = 15665106 | pmc = 547821 | doi = 10.1073/pnas.0405488102 | bibcode = 2005PNAS..102.1655H | doi-access = free }}</ref>
# [[costamere]]s, where it binds to [[zyxin]], integrin linked kinase ([[ILK]]) and beta1-[[spectrin]];<ref name=a13/><ref name=a17>{{cite journal | vauthors = Flick MJ, Konieczny SF | title = The muscle regulatory and structural protein MLP is a cytoskeletal binding partner of betaI-spectrin | journal = Journal of Cell Science | volume = 113 | issue = 9 | pages = 1553–64 | date = May 2000 | doi = 10.1242/jcs.113.9.1553 | pmid = 10751147 }}</ref><ref name=a18>{{cite journal | vauthors = Postel R, Vakeel P, Topczewski J, Knöll R, Bakkers J | title = Zebrafish integrin-linked kinase is required in skeletal muscles for strengthening the integrin-ECM adhesion complex | journal = Developmental Biology | volume = 318 | issue = 1 | pages = 92–101 | date = June 2008 | pmid = 18436206 | doi = 10.1016/j.ydbio.2008.03.024 | doi-access =  }}</ref> 
# [[intercalated discs]], where it associates with the [[nebulin]]-related anchoring protein ([[NRAP]]);<ref name=a19>{{cite journal | vauthors = Ehler E, Horowits R, Zuppinger C, Price RL, Perriard E, Leu M, Caroni P, Sussman M, Eppenberger HM, Perriard JC | title = Alterations at the intercalated disk associated with the absence of muscle LIM protein | journal = The Journal of Cell Biology | volume = 153 | issue = 4 | pages = 763–72 | date = May 2001 | pmid = 11352937 | pmc = 2192386 | doi = 10.1083/jcb.153.4.763 }}</ref> 
# [[Cell nucleus|nucleus]], where it binds to the transcription factors [[MyoD]], [[myogenin]] and [[MRF4]].<ref name=a20>{{cite journal | vauthors = Kong Y, Flick MJ, Kudla AJ, Konieczny SF | title = Muscle LIM protein promotes myogenesis by enhancing the activity of MyoD | journal = Molecular and Cellular Biology | volume = 17 | issue = 8 | pages = 4750–60 | date = August 1997 | pmid = 9234731 | pmc = 232327 | doi = 10.1128/mcb.17.8.4750 }}</ref> 
[[Sarcomere|M-line]] as well as [[plasma membrane]] localization of MLP has also been observed, however, the protein associations mediating this subcellular distribution are currently unknown.<ref name=a12/><ref name=a21>{{cite journal | vauthors = Knöll R, Kostin S, Klede S, Savvatis K, Klinge L, Stehle I, Gunkel S, Kötter S, Babicz K, Sohns M, Miocic S, Didié M, Knöll G, Zimmermann WH, Thelen P, Bickeböller H, Maier LS, Schaper W, Schaper J, Kraft T, Tschöpe C, Linke WA, Chien KR | title = A common MLP (muscle LIM protein) variant is associated with cardiomyopathy | journal = Circulation Research | volume = 106 | issue = 4 | pages = 695–704 | date = March 2010 | pmid = 20044516 | doi = 10.1161/CIRCRESAHA.109.206243 | doi-access = free }}</ref> 
These diverse localization patterns and binding partners of MLP suggest a multitude of roles relating both to the striated myocyte [[cytoskeleton]] and the nucleus.<ref name=a22>{{cite journal | vauthors = Boateng SY, Senyo SE, Qi L, Goldspink PH, Russell B | title = Myocyte remodeling in response to hypertrophic stimuli requires nucleocytoplasmic shuttling of muscle LIM protein | journal = Journal of Molecular and Cellular Cardiology | volume = 47 | issue = 4 | pages = 426–35 | date = October 2009 | pmid = 19376126 | pmc = 2739242 | doi = 10.1016/j.yjmcc.2009.04.006 }}</ref> The role of MLP in each of these two cellular compartments appears to be dynamic, with studies demonstrating nucleocytoplasmic shuttling, driven by its nuclear localization signal, over time and under different conditions.<ref name=a22/>

== Function ==
In the nucleus, MLP acts as a positive regulator of [[myogenesis]] and promotes myogenic differentiation.<ref name=a3/> Overexpression of MLP enhances myotube differentiation, an effect attributed to the direct association of MLP with muscle specific transcription factors such as MyoD, myogenin and MRF4 and consequently the transcriptional control of fundamental muscle-specific genes.<ref name=a3/><ref name=a7/><ref name=a20/> 
In the cytoplasm, MLP is an important [[scaffold protein]], implicated in various cytoskeletal macromolecular complexes, at the sarcomeric Z-line, the costameres, and the [[microfilaments]].<ref name=a6/><ref name=a7/><ref name=a11/><ref name=a13/><ref name=a14/><ref name=a15/><ref name=a16/>  At the Z-line, MLP  interacts with different Z-line components <ref name=a6/><ref name=a7/><ref name=a11/><ref name=a13/><ref name=a14/><ref name=a15/><ref name=a16/><ref name=a23>{{cite journal | vauthors = Clark KA, Bland JM, Beckerle MC | title = The Drosophila muscle LIM protein, Mlp84B, cooperates with D-titin to maintain muscle structural integrity | journal = Journal of Cell Science | volume = 120 | issue = Pt 12 | pages = 2066–77 | date = June 2007 | pmid = 17535853 | doi = 10.1242/jcs.000695 | doi-access =  | s2cid = 23791613 }}</ref><ref name=a24>{{cite journal | vauthors = Clark KA, Kadrmas JL | title = Drosophila melanogaster muscle LIM protein and alpha-actinin function together to stabilize muscle cytoarchitecture: a potential role for Mlp84B in actin-crosslinking | journal = Cytoskeleton | volume = 70 | issue = 6 | pages = 304–16 | date = June 2013 | pmid = 23606669 | pmc = 3716849 | doi = 10.1002/cm.21106 }}</ref> and acts as a scaffold protein promoting the assembly of macromolecular complexes along sarcomeres and [[actin]]-based cytoskeleton <ref name=a6/><ref name=a17/><ref name=a19/><ref name=a25>{{cite journal | vauthors = Arber S, Caroni P | title = Specificity of single LIM motifs in targeting and LIM/LIM interactions in situ | journal = Genes & Development | volume = 10 | issue = 3 | pages = 289–300 | date = February 1996 | pmid = 8595880 | doi = 10.1101/gad.10.3.289 | doi-access = free }}</ref><ref name=a26>{{cite journal | vauthors = Arber S, Hunter JJ, Ross J, Hongo M, Sansig G, Borg J, Perriard JC, Chien KR, Caroni P | title = MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure | journal = Cell | volume = 88 | issue = 3 | pages = 393–403 | date = February 1997 | pmid = 9039266 | doi = 10.1016/s0092-8674(00)81878-4 | s2cid = 16597001 | doi-access = free }}</ref> Moreover, since the Z-line acts as a stretch sensor,<ref name=a27>{{cite journal | vauthors = Frank D, Frey N | title = Cardiac Z-disc signaling network | journal = The Journal of Biological Chemistry | volume = 286 | issue = 12 | pages = 9897–904 | date = March 2011 | pmid = 21257757 | pmc = 3060542 | doi = 10.1074/jbc.R110.174268 | doi-access = free }}</ref><ref name=a28>{{cite journal | vauthors = Gautel M | title = The sarcomeric cytoskeleton: who picks up the strain? | journal = Current Opinion in Cell Biology | volume = 23 | issue = 1 | pages = 39–46 | date = February 2011 | pmid = 21190822 | doi = 10.1016/j.ceb.2010.12.001 }}</ref><ref name=a29>{{cite journal | vauthors = Luther PK | title = The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling | journal = Journal of Muscle Research and Cell Motility | volume = 30 | issue = 5–6 | pages = 171–85 | date = 2009 | pmid = 19830582 | pmc = 2799012 | doi = 10.1007/s10974-009-9189-6 }}</ref><ref name=a30>{{cite journal | vauthors = Buyandelger B, Ng KE, Miocic S, Gunkel S, Piotrowska I, Ku CH, Knöll R | title = Genetics of mechanosensation in the heart | journal = Journal of Cardiovascular Translational Research | volume = 4 | issue = 3 | pages = 238–44 | date = June 2011 | pmid = 21360311 | pmc = 3098994 | doi = 10.1007/s12265-011-9262-6 }}</ref> MLP is believed to be involved in mechano-signaling processes. Indeed, [[cardiomyocytes]] from MLP transgenic or [[knock-out mouse]] exhibit defective intrinsic stretch responses, due to selective loss of passive stretch sensing.<ref name=a6/><ref name=a21/> 
At the [[costamere]]s, another region implicated in force transmission, MLP is thought to be contributing in mechanosensing through its interactions with β1 [[spectrin]] and [[zyxin]]. However, the precise role of MLP at the costameres has not been extensively investigated yet.

At the microfilaments, MLP is implicated in [[actin remodeling]] (or actin dynamics) through its interaction with [[cofilin]]-2 ([[CFL2 (gene)|CFL2]]). Binding of MLP to CFL2 enhances the CFL2-dependent F-actin depolymerization,<ref name=a14/> with a recent study demonstrating that MLP can act directly on actin cytoskeleton dynamics through direct binding that stabilizes and crosslinks [[actin filaments]] into bundles.<ref name=a31>{{cite journal | vauthors = Hoffmann C, Moreau F, Moes M, Luthold C, Dieterle M, Goretti E, Neumann K, Steinmetz A, Thomas C | title = Human muscle LIM protein dimerizes along the actin cytoskeleton and cross-links actin filaments | journal = Molecular and Cellular Biology | volume = 34 | issue = 16 | pages = 3053–65 | date = August 2014 | pmid = 24934443 | pmc = 4135597 | doi = 10.1128/MCB.00651-14 }}</ref>

Additionally, MLP is indirectly related to calcium homeostasis and energy metabolism. Specifically, acetylation of MLP increases the calcium sensitivity of myofilaments and regulates [[contractility]],<ref name=a11/> while the absence of MLP causes alterations in [[calcium signaling]] (intracellular calcium handling) with defects in [[excitation-contraction coupling]].<ref name=a32>{{cite journal | vauthors = Esposito G, Santana LF, Dilly K, Cruz JD, Mao L, Lederer WJ, Rockman HA | s2cid = 2090600 | title = Cellular and functional defects in a mouse model of heart failure | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 279 | issue = 6 | pages = H3101–12 | date = December 2000 | pmid = 11087268 | doi = 10.1152/ajpheart.2000.279.6.H3101 }}</ref><ref name=a33>{{cite journal | vauthors = Kemecsei P, Miklós Z, Bíró T, Marincsák R, Tóth BI, Komlódi-Pásztor E, Barnucz E, Mirk E, Van der Vusse GJ, Ligeti L, Ivanics T | title = Hearts of surviving MLP-KO mice show transient changes of intracellular calcium handling | journal = Molecular and Cellular Biochemistry | volume = 342 | issue = 1–2 | pages = 251–60 | date = September 2010 | pmid = 20490897 | doi = 10.1007/s11010-010-0492-8 | s2cid = 33877175 | hdl = 2437/104103 | hdl-access = free }}</ref><ref name=a34>{{cite journal | vauthors = Su Z, Yao A, Zubair I, Sugishita K, Ritter M, Li F, Hunter JJ, Chien KR, Barry WH | s2cid = 12682659 | title = Effects of deletion of muscle LIM protein on myocyte function | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 280 | issue = 6 | pages = H2665–73 | date = June 2001 | pmid = 11356623 | doi = 10.1152/ajpheart.2001.280.6.H2665 | doi-access = free }}</ref> Furthermore, lack of MLP leads to local loss of [[mitochondria]] and energy deficiency.<ref name=a35>{{cite journal | vauthors = van den Bosch BJ, van den Burg CM, Schoonderwoerd K, Lindsey PJ, Scholte HR, de Coo RF, van Rooij E, Rockman HA, Doevendans PA, Smeets HJ | title = Regional absence of mitochondria causing energy depletion in the myocardium of muscle LIM protein knockout mice | journal = Cardiovascular Research | volume = 65 | issue = 2 | pages = 411–8 | date = February 2005 | pmid = 15639480 | doi = 10.1016/j.cardiores.2004.10.025 | doi-access = free }}</ref>

== Animal studies ==

In rodents, MLP is transiently expressed in [[amacrine cell]]s of the [[retina]] during postnatal development.<ref>{{cite journal | vauthors = Levin E, Leibinger M, Andreadaki A, Fischer D | title = Neuronal expression of muscle LIM protein in postnatal retinae of rodents | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100756 | date = 2014-06-19 | pmid = 24945278 | pmc = 4063954 | doi = 10.1371/journal.pone.0100756 | bibcode = 2014PLoSO...9j0756L | doi-access = free }}</ref> In the adult nervous system it is expressed upon axonal injury,<ref>{{cite journal | vauthors = Levin E, Andreadaki A, Gobrecht P, Bosse F, Fischer D | title = Nociceptive DRG neurons express muscle lim protein upon axonal injury | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 643 | date = April 2017 | pmid = 28377582 | pmc = 5428558 | doi = 10.1038/s41598-017-00590-1 | bibcode = 2017NatSR...7..643L }}</ref> where it plays an important role during regenerative processes, functioning as an actin cross-linker, thereby facilitating [[filopodia]] formation and increasing growth cone motility.<ref name = "Levin_2019" />

== Clinical significance ==
MLP is directly associated with striated muscle diseases.<ref name="Vafiadaki_2015">{{cite journal | vauthors = Vafiadaki E, Arvanitis DA, Sanoudou D | title = Muscle LIM Protein: Master regulator of cardiac and skeletal muscle functions | journal = Gene | volume = 566 | issue = 1 | pages = 1–7 | date = July 2015 | pmid = 25936993 | doi = 10.1016/j.gene.2015.04.077 | department = Review | pmc = 6660132 }}</ref> [[Mutations]] in the CSRP3 gene have been detected in patients with [[dilated cardiomyopathy]] (DCM) [e.g. G72R and K69R], and [[hypertrophic cardiomyopathy]] (HCM) [e.g. L44P, S46R, S54R/E55G, C58G, R64C, Y66C, Q91L, K42/fs165], while the most frequent MLP mutation, W4R, has been found in both of these patient populations.<ref name=a6/><ref name=a10/><ref name=a21/><ref name=a36>{{cite journal | vauthors = Geier C, Gehmlich K, Ehler E, Hassfeld S, Perrot A, Hayess K, Cardim N, Wenzel K, Erdmann B, Krackhardt F, Posch MG, Osterziel KJ, Bublak A, Nägele H, Scheffold T, Dietz R, Chien KR, Spuler S, Fürst DO, Nürnberg P, Ozcelik C | title = Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy | journal = Human Molecular Genetics | volume = 17 | issue = 18 | pages = 2753–65 | date = September 2008 | pmid = 18505755 | doi = 10.1093/hmg/ddn160 | doi-access = free }}</ref><ref name=a37>{{cite journal | vauthors = Geier C, Perrot A, Ozcelik C, Binner P, Counsell D, Hoffmann K, Pilz B, Martiniak Y, Gehmlich K, van der Ven PF, Fürst DO, Vornwald A, von Hodenberg E, Nürnberg P, Scheffold T, Dietz R, Osterziel KJ | title = Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy | journal = Circulation | volume = 107 | issue = 10 | pages = 1390–5 | date = March 2003 | pmid = 12642359 | doi = 10.1161/01.cir.0000056522.82563.5f | doi-access = free }}</ref><ref name=a38>{{cite journal | vauthors = Hershberger RE, Parks SB, Kushner JD, Li D, Ludwigsen S, Jakobs P, Nauman D, Burgess D, Partain J, Litt M | title = Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy | journal = Clinical and Translational Science | volume = 1 | issue = 1 | pages = 21–6 | date = May 2008 | pmid = 19412328 | pmc = 2633921 | doi = 10.1111/j.1752-8062.2008.00017.x }}</ref><ref name=a39>{{cite journal | vauthors = Mohapatra B, Jimenez S, Lin JH, Bowles KR, Coveler KJ, Marx JG, Chrisco MA, Murphy RT, Lurie PR, Schwartz RJ, Elliott PM, Vatta M, McKenna W, Towbin JA, Bowles NE | title = Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis | journal = Molecular Genetics and Metabolism | volume = 80 | issue = 1–2 | pages = 207–15 | date = 2002 | pmid = 14567970 | doi = 10.1016/s1096-7192(03)00142-2 }}</ref> Biochemical and functional studies have been performed for some of these mutant proteins, and reveal aberrant localization and interaction patterns, leading to impaired molecular and cellular functions. For example, the W4R mutation abolishes the MLP/T-cap interaction, leading to mislocalization of T-cap, Z-line instability and severe sarcomeric structural defects.<ref name=a6/> The C58G mutation causes reduced protein stability due to enhanced [[ubiquitin]]-dependent [[proteasome]] degradation<ref name=a36/> while the K69L mutation, which is within the predicted nuclear localization signal of MLP, abolishes the MLP/α-actinin interaction and causes altered subcellular distribution of the mutant protein, showing predominant perinuclear localization.<ref name=a39/> 
Alterations in the protein expression levels of MLP, its [[oligomerization]] or [[Protein splicing|splicing]] have also been described in human cardiac and skeletal muscle diseases: both MLP protein levels and oligomerization are down-regulated in human [[heart failure]],<ref name=a12/><ref name=a15/> while MLP levels are significantly changed in different skeletal [[myopathies]], including [[facioscapulohumeral muscular dystrophy]], [[nemaline myopathy]] and limb girdle muscular dystrophy type 2B.<ref name=a40>{{cite journal | vauthors = Sanoudou D, Corbett MA, Han M, Ghoddusi M, Nguyen MA, Vlahovich N, Hardeman EC, Beggs AH | title = Skeletal muscle repair in a mouse model of nemaline myopathy | journal = Human Molecular Genetics | volume = 15 | issue = 17 | pages = 2603–12 | date = September 2006 | pmid = 16877500 | pmc = 3372923 | doi = 10.1093/hmg/ddl186 }}</ref><ref name=a41>{{cite journal | vauthors = von der Hagen M, Laval SH, Cree LM, Haldane F, Pocock M, Wappler I, Peters H, Reitsamer HA, Hoger H, Wiedner M, Oberndorfer F, Anderson LV, Straub V, Bittner RE, Bushby KM | title = The differential gene expression profiles of proximal and distal muscle groups are altered in pre-pathological dysferlin-deficient mice | journal = Neuromuscular Disorders | volume = 15 | issue = 12 | pages = 863–77 | date = December 2005 | pmid = 16288871 | doi = 10.1016/j.nmd.2005.09.002 | s2cid = 8690648 }}</ref><ref name=a42>{{cite journal | vauthors = Winokur ST, Chen YW, Masny PS, Martin JH, Ehmsen JT, Tapscott SJ, van der Maarel SM, Hayashi Y, Flanigan KM | title = Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation | journal = Human Molecular Genetics | volume = 12 | issue = 22 | pages = 2895–907 | date = November 2003 | pmid = 14519683 | doi = 10.1093/hmg/ddg327 | doi-access = free }}</ref> Moreover, significant changes in MLP-b protein expression levels, as well as deregulation of the MLP:MLP-b ratio have been detected in [[limb girdle muscular dystrophy]] type 2A, [[Duchenne muscular dystrophy]] and [[dermatomyositis]] patients.<ref name=a7/>

== Animal models ==
Animal models are providing insight into MLP's function in striated muscle. Ablation of Mlp (MLP-/-) in mice affects all striated muscles, although the cardiac phenotype is more severe, leading to alterations in cardiac pressure and volume, aberrant [[contractility]], development of dilated cardiomyopathy with hypertrophy and progressive heart failure.<ref name=a26/><ref name=a32/><ref name=a43>{{cite journal | vauthors = Omens JH, Usyk TP, Li Z, McCulloch AD | s2cid = 9501573 | title = Muscle LIM protein deficiency leads to alterations in passive ventricular mechanics | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 282 | issue = 2 | pages = H680–7 | date = February 2002 | pmid = 11788418 | doi = 10.1152/ajpheart.00773.2001 }}</ref> At the histological level there is dramatic disruption of the cardiomyocyte [[cytoarchitecture]] at multiple levels, and pronounced [[fibrosis]].<ref name=a19/><ref name=a26/><ref name=a34/><ref name=a44>{{cite journal | vauthors = Wilson AJ, Schoenauer R, Ehler E, Agarkova I, Bennett PM | title = Cardiomyocyte growth and sarcomerogenesis at the intercalated disc | journal = Cellular and Molecular Life Sciences | volume = 71 | issue = 1 | pages = 165–81 | date = January 2014 | pmid = 23708682 | pmc = 3889684 | doi = 10.1007/s00018-013-1374-5 }}</ref> Other cellular changes included alterations in intracellular calcium handling, local loss of mitochondria and energy deficiency.<ref name=a32/><ref name=a33/><ref name=a34/>
Crossing MLP-/- mice with [[phospholamban]] (PLN) -/-, or [[β2-adrenergic receptor]] (β2-AR) -/-, or [[angiotensin]] II type 1a receptor (AT1a) -/-, or β-adrenergic receptor kinase 1 inhibitor ([[bARK1]]) -/- mice, as well as overexpressing calcineurin rescued their cardiac function, through a series of only partly understood molecular mechanisms.<ref name=a45>{{cite journal | vauthors = Fajardo G, Zhao M, Urashima T, Farahani S, Hu DQ, Reddy S, Bernstein D | title = Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice | journal = Journal of Molecular and Cellular Cardiology | volume = 63 | pages = 155–64 | date = October 2013 | pmid = 23920331 | pmc = 3791213 | doi = 10.1016/j.yjmcc.2013.07.016 }}</ref><ref name=a46>{{cite journal | vauthors = Heineke J, Wollert KC, Osinska H, Sargent MA, York AJ, Robbins J, Molkentin JD | title = Calcineurin protects the heart in a murine model of dilated cardiomyopathy | journal = Journal of Molecular and Cellular Cardiology | volume = 48 | issue = 6 | pages = 1080–7 | date = June 2010 | pmid = 19854199 | pmc = 2891089 | doi = 10.1016/j.yjmcc.2009.10.012 }}</ref><ref name=a47>{{cite journal | vauthors = Minamisawa S, Hoshijima M, Chu G, Ward CA, Frank K, Gu Y, Martone ME, Wang Y, Ross J, Kranias EG, Giles WR, Chien KR | title = Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy | journal = Cell | volume = 99 | issue = 3 | pages = 313–22 | date = October 1999 | pmid = 10555147 | doi = 10.1016/s0092-8674(00)81662-1 | s2cid = 1299470 | doi-access = free }}</ref><ref name=a48>{{cite journal | vauthors = Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross J, Lefkowitz RJ, Koch WJ | title = Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 12 | pages = 7000–5 | date = June 1998 | pmid = 9618528 | pmc = 22717 | doi = 10.1073/pnas.95.12.7000 | bibcode = 1998PNAS...95.7000R | doi-access = free }}</ref><ref name=a49>{{cite journal | vauthors = Yamamoto R, Akazawa H, Ito K, Toko H, Sano M, Yasuda N, Qin Y, Kudo Y, Sugaya T, Chien KR, Komuro I | title = Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice | journal = Circulation Journal | volume = 71 | issue = 12 | pages = 1958–64 | date = December 2007 | pmid = 18037754 | doi = 10.1253/circj.71.1958 | doi-access = free }}</ref> Conversely crossing MLP-/- mice with [[β1-adrenergic receptor]] (β1-AR) -/- mice was lethal, while crossing MLP-/- mice with calcineurin -/- mice, enhanced fibrosis and [[cardiomyopathy]].<ref name=a45/><ref name=a46/> A [[gene knockin]] mouse model harboring the human MLP-W4R mutation developed HCM and heart failure, while ultrastructural analysis of its cardiac tissue revealed [[myocardial disarray]] and significant fibrosis, increased nuclear localization of MLP concomitantly with reduced sarcomeric Z-line distribution.<ref name=a21/> 
Alterations in MLP nucleocytoplasmic shuttling, which are possibly modulated by changes in its oligomerization status, have also been implicated in hypertrophy and heart failure, independently of mutations.<ref name=a12/><ref name=a22/>
Studies in [[Drosophila]] revealed that genetic ablation of Mlp84B, the Drosophila homolog of MLP, was associated with pupal lethality and impaired muscle function.<ref name=a23/> Mechanical studies of Mlp84B-null flight muscles indicate that loss of Mlp84B results in decreased muscle stiffness and power generation.<ref name=a50>{{cite journal | vauthors = Clark KA, Lesage-Horton H, Zhao C, Beckerle MC, Swank DM | title = Deletion of Drosophila muscle LIM protein decreases flight muscle stiffness and power generation | journal = American Journal of Physiology. Cell Physiology | volume = 301 | issue = 2 | pages = C373–82 | date = August 2011 | pmid = 21562304 | pmc = 3154547 | doi = 10.1152/ajpcell.00206.2010 }}</ref> Cardiac-specific ablation of Mlp84B caused decreased lifespan, impaired diastolic function and disturbances in cardiac rhythm.<ref name=a51>{{cite journal | vauthors = Mery A, Taghli-Lamallem O, Clark KA, Beckerle MC, Wu X, Ocorr K, Bodmer R | title = The Drosophila muscle LIM protein, Mlp84B, is essential for cardiac function | journal = The Journal of Experimental Biology | volume = 211 | issue = Pt 1 | pages = 15–23 | date = January 2008 | pmid = 18083727 | doi = 10.1242/jeb.012435 | doi-access = free }}</ref> 
Overall, these animal models have provided critical evidence on the functional significance of MLP in striated muscle physiology and pathophysiology.

==Notes==
{{Academic-written review|Q=Q38456293}}

== References ==
{{reflist|33em}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hyper-card  GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview]
* {{UCSC gene info|CSRP3}}
* {{UCSC gene info|LMO4}}
* {{PDBe-KB2|P50461|Cysteine and glycine-rich protein 3}}