Abstract
We identified the first homozygous and hence recessive mutation in the myotilin gene (MYOT) in a family affected by a severe myofibrillar myopathy (MFM). MFM is a rare, progressive and devastating disease of human skeletal muscle with distinct histopathological pattern of protein aggregates and myofibrillar degeneration. So far, only heterozygous missense mutations in MYOT have been associated with autosomal dominant myofibrillar myopathy, limb-girdle muscular dystrophy type 1A and distal myopathy. Myotilin itself is highly expressed in skeletal and cardiac muscle and is localized at the Z-disc and therefore interacts in sarcomere assembly. We performed whole-exome sequencing in a German family clinically diagnosed with MFM and identified a homozygous mutation in exon 2, c.16C > G (p.Arg6Gly). Using laser microdissection followed by quantitative mass spectrometry, we identified the myotilin protein as one component showing the highest increased abundance in the aggregates in the index patient. We suggest that the combined approach has a high potential as a new tool for the confirmation of unclassified variants which are found in whole-exome sequencing approaches.
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References
Schroder R, Schoser B (2009) Myofibrillar myopathies: a clinical and myopathological guide. Brain Pathol 19(3):483–492
Selcen D (2011) Myofibrillar myopathies. Neuromuscul Disord 21(3):161–171
Selcen D (2010) Myofibrillar myopathies. Curr Opin Neurol 23(5):477–481. doi:10.1097/WCO.0b013e32833d38b0
Selcen D, Engel AG (2011) Myofibrillar myopathies. Handb Clin Neurol 101:143–154
Selcen D, Ohno K, Engel AG (2004) Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients. Brain 127(Pt 2):439–451. doi:10.1093/brain/awh052
Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O (1999) Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum Mol Genet 8(7):1329–1336
Salmikangas P, van der Ven PF, Lalowski M, Taivainen A, Zhao F, Suila H, Schroder R, Lappalainen P, Furst DO, Carpen O (2003) Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum Mol Genet 12(2):189–203
Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L (2005) The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins. J Cell Sci 118(Pt 16):3739–3749
van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schroder R, Carpen O, Furst DO (2000) Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin. J Cell Biol 151(2):235–248
Berciano J, Gallardo E, Dominguez-Perles R, Garcia A, Garcia-Barredo R, Combarros O, Infante J, Illa I (2008) Autosomal-dominant distal myopathy with a myotilin S55F mutation: sorting out the phenotype. J Neurol Neurosurg Psychiatry 79(2):205–208
Foroud T, Pankratz N, Batchman AP, Pauciulo MW, Vidal R, Miravalle L, Goebel HH, Cushman LJ, Azzarelli B, Horak H, Farlow M, Nichols WC (2005) A mutation in myotilin causes spheroid body myopathy. Neurology 65(12):1936–1940. doi:10.1212/01.wnl.0000188872.28149.9a
Hauser MA, Conde CB, Kowaljow V, Zeppa G, Taratuto AL, Torian UM, Vance J, Pericak-Vance MA, Speer MC, Rosa AL (2002) Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet 71(6):1428–1432
Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A, Bartoloni L, Gilchrist JM, Stajich JM, Gaskell PC, Gilbert JR, Vance JM, Pericak-Vance MA, Carpen O, Westbrook CA, Speer MC (2000) Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 9(14):2141–2147
Olive M, Goldfarb LG, Shatunov A, Fischer D, Ferrer I (2005) Myotilinopathy: refining the clinical and myopathological phenotype. Brain 128(Pt 10):2315–2326
Reilich P, Krause S, Schramm N, Klutzny U, Bulst S, Zehetmayer B, Schneiderat P, Walter MC, Schoser B, Lochmuller H (2011) A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A). J Neurol 258(8):1437–1444. doi:10.1007/s00415-011-5953-9
Penisson-Besnier I, Talvinen K, Dumez C, Vihola A, Dubas F, Fardeau M, Hackman P, Carpen O, Udd B (2006) Myotilinopathy in a family with late onset myopathy. Neuromuscul Disord 16(7):427–431
Vattemi G, Neri M, Piffer S, Vicart P, Gualandi F, Marini M, Guglielmi V, Filosto M, Tonin P, Ferlini A, Tomelleri G (2011) Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy. Acta Myol 30(2):121–126
Feldkirchner S, Schessl J, Muller S, Schoser B, Hanisch FG (2012) Patient-specific protein aggregates in myofibrillar myopathies: laser microdissection and differential proteomics for identification of plaque components. Proteomics 12(23–24):3598–3609. doi:10.1002/pmic.201100559
Selcen D, Engel AG (2004) Mutations in myotilin cause myofibrillar myopathy. Neurology 62(8):1363–1371
Shalaby S, Mitsuhashi H, Matsuda C, Minami N, Noguchi S, Nonaka I, Nishino I, Hayashi YK (2009) Defective myotilin homodimerization caused by a novel mutation in MYOT exon 9 in the first Japanese limb girdle muscular dystrophy 1A patient. J Neuropathol Exp Neurol 68(6):701–707. doi:10.1097/NEN.0b013e3181a7f703
Feldkirchner S, Walter MC, Muller S, Kubny C, Krause S, Kress W, Hanisch FG, Schoser B, Schessl J (2013) Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy. Neuromuscul Disord 23:418–426
Kley RA, Maerkens A, Leber Y, Theis V, Schreiner A, van der Ven PF, Uszkoreit J, Stephan C, Eulitz S, Euler N, Kirschner J, Muller K, Meyer HE, Tegenthoff M, Furst DO, Vorgerd M, Muller T, Marcus K (2013) A combined laser microdissection and mass spectrometry approach reveals new disease relevant proteins accumulating in aggregates of filaminopathy patients. Mol Cell Proteomics 12(1):215–227
Acknowledgments
We would like to thank the patients reported here for their participation and encouragement. We thank Ursula Klutzny and Maria Schmuck for the technical assistance. We also would like to thank Dr. Michael A. Hauser (Duke University Medical Center, Durham, NC, USA) for the myotilin antibody. J.S., F.G.H., W.K. and B.S. are supported by the German Research Association (DFG, FOR1228) and are members of the German network on muscular dystrophies (MD-NET funded by BMBF, Bonn, Germany; www.md-net.org). MD-NET is a partner of TREAT-NMD (EC, 6th FP, proposal no. 036825; www.treat-nmd.eu).
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The authors have reported no conflicts of interest.
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Schessl, J., Bach, E., Rost, S. et al. Novel recessive myotilin mutation causes severe myofibrillar myopathy. Neurogenetics 15, 151–156 (2014). https://doi.org/10.1007/s10048-014-0410-4
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DOI: https://doi.org/10.1007/s10048-014-0410-4