Novel recessive myotilin mutation causes severe myofibrillar myopathy
- 487 Downloads
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.
KeywordsMyotilin Myofibrillar myopathy Recessive muscle disease Whole-exome sequencing
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).
The authors have reported no conflicts of interest.
- 7.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):189–203PubMedCrossRefGoogle Scholar
- 9.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):235–248PubMedCentralPubMedCrossRefGoogle Scholar
- 13.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):2141–2147PubMedCrossRefGoogle Scholar
- 15.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 PubMedCrossRefGoogle Scholar
- 18.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 PubMedCrossRefGoogle Scholar
- 20.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 PubMedCrossRefGoogle Scholar
- 22.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):215–227PubMedCentralPubMedCrossRefGoogle Scholar