K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity

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dc.contributor.authorMokbel, Nen_AU
dc.contributor.authorIlkovski, Ben_AU
dc.contributor.authorKreissl, Men_AU
dc.contributor.authorMemo, Men_AU
dc.contributor.authorJeffries, CMen_AU
dc.contributor.authorMarttila, Men_AU
dc.contributor.authorLehtokari, VLen_AU
dc.contributor.authorLemola, Een_AU
dc.contributor.authorGrönholm, Men_AU
dc.contributor.authorYang, Nen_AU
dc.contributor.authorMenard, Den_AU
dc.contributor.authorMarcorelles, Pen_AU
dc.contributor.authorEchaniz-Laguna, Aen_AU
dc.contributor.authorReimann, Jen_AU
dc.contributor.authorVainzof, Men_AU
dc.contributor.authorMonnier, Nen_AU
dc.contributor.authorRavenscroft, Gen_AU
dc.contributor.authorMcNamara, Een_AU
dc.contributor.authorNowak, KJen_AU
dc.contributor.authorLaing, NGen_AU
dc.contributor.authorWallgren-Pettersson, Cen_AU
dc.contributor.authorTrewhella, Jen_AU
dc.contributor.authorMarston, Sen_AU
dc.contributor.authorOttenheijm, Cen_AU
dc.contributor.authorNorth, KNen_AU
dc.contributor.authorClarke, NFen_AU
dc.date.accessioned2013-03-12T00:46:40Zen_AU
dc.date.available2013-03-12T00:46:40Zen_AU
dc.date.issued2012-11-15en_AU
dc.date.statistics2013-03-12en_AU
dc.description.abstractMutations in the TPM2 gene, which encodes β-tropomyosin, are an established cause of several congenital skeletal myopathies and distal arthrogryposis. We have identified a TPM2 mutation, p.K7del, in five unrelated families with nemaline myopathy and a consistent distinctive clinical phenotype. Patients develop large joint contractures during childhood, followed by slowly progressive skeletal muscle weakness during adulthood. The TPM2 p.K7del mutation results in the loss of a highly conserved lysine residue near the N-terminus of β-tropomyosin, which is predicted to disrupt head-to-tail polymerization of tropomyosin. Recombinant K7del-β-tropomyosin incorporates poorly into sarcomeres in C2C12 myotubes and has a reduced affinity for actin. Two-dimensional gel electrophoresis of patient muscle and primary patient cultured myotubes showed that mutant protein is expressed but incorporates poorly into sarcomeres and likely accumulates in nemaline rods. In vitro studies using recombinant K7del-β-tropomyosin and force measurements from single dissected patient myofibres showed increased myofilament calcium sensitivity. Together these data indicate that p.K7del is a common recurrent TPM2 mutation associated with mild nemaline myopathy. The p.K7del mutation likely disrupts head-to-tail polymerization of tropomyosin, which impairs incorporation into sarcomeres and also affects the equilibrium of the troponin/tropomyosin-dependent calcium switch of muscle. Joint contractures may stem from chronic muscle hypercontraction due to increased myofibrillar calcium sensitivity while declining strength in adulthood likely arises from other mechanisms, such as myofibre decompensation and fatty infiltration. These results suggest that patients may benefit from therapies that reduce skeletal muscle calcium sensitivity, and we highlight late muscle decompensation as an important cause of morbidity. © 2012, Oxford University Pressen_AU
dc.identifier.citationMokbel, N., Ilkovski, B., Kreissl, M., Memo, M., Jeffries, G.M., Marttila, M., Lehtokari, V-L., Lemola, E., Grönholm, E., Yang, N., Menard, D., Marcorelles, P., Echaniz-Laguna, A., Reimann, J., Vainzof, M., Monnier, N., Ravenscroft, C., McNamara, E., Nowak, K.J., Laing, N.G., Wallgren-Pettersson, C., Trewhella, J., Marston, S., Ottenheijm, C., North, K.N., Clarke, N.F. (2012). K7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivity. Brain 136(2), 494-507. doi:10.1093/brain/aws348en_AU
dc.identifier.govdoc4892en_AU
dc.identifier.issn0006-8950en_AU
dc.identifier.issue2en_AU
dc.identifier.journaltitleBrainen_AU
dc.identifier.pagination494-507en_AU
dc.identifier.urihttp://dx.doi.org/10.1093/brain/aws348en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/4516en_AU
dc.identifier.volume136en_AU
dc.language.isoenen_AU
dc.publisherOxford University Pressen_AU
dc.subjectTropomyosinen_AU
dc.subjectMusclesen_AU
dc.subjectActinen_AU
dc.subjectBone jointsen_AU
dc.subjectPolymerizationen_AU
dc.subjectCalciumen_AU
dc.titleK7del is a common TPM2 gene mutation associated with nemaline myopathy and raised myofibre calcium sensitivityen_AU
dc.typeJournal Articleen_AU
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