Molecular Neurobiology

, Volume 53, Issue 8, pp 5097–5102 | Cite as

Identification of a Novel Mutation in the Titin Gene in a Chinese Family with Limb-Girdle Muscular Dystrophy 2J

  • Wen Zheng
  • Han Chen
  • Xiong Deng
  • Lamei Yuan
  • Yan Yang
  • Zhi Song
  • Zhijian Yang
  • Yuan Wu
  • Hao Deng


Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of genetic myopathies characterized by progressive proximal pelvic and/or shoulder girdle muscle weakness, with the onset ages ranging from early childhood to late adulthood. The identification of these dystrophies through genetic testing will not only inform long-term prognosis but will also assist in directing care more efficiently, including more frequent cardiorespiratory monitoring and prophylactic treatments. The aim of this study was to identify the responsible gene in a five-generation Chinese Han pedigree with autosomal recessive LGMD. Exome sequencing was conducted and a novel mutation c.107788T>C (p.W35930R) in the titin gene (TTN) was identified. The mutation co-segregated with the disorder in the family and was absent in normal controls. Our discovery broadens the mutation spectrum of the TTN gene associated with LGMD2J.


Limb-girdle muscular dystrophies Exome sequencing TTN Mutation Genetic testing 



Limb-girdle muscular dystrophies


Creatine kinase




The titin gene


Exome sequencing project


Sorting intolerant from tolerant


Polymorphism phenotyping version 2


Tibial muscular dystrophy


Copy number variation


Single nucleotide polymorphisms



This study was supported by grants 81441033 and 81271921 from the National Natural Science Foundation of China (H.D.), grant 2015JJ4088 from the Natural Science Foundation of Hunan Province, China (W.Z.), grant 2015zzts318 from the Fundamental Research Funds of Central South University, China, grant for the Foster Key Subject of the Third Xiangya Hospital Clinical Laboratory Diagnostics (H.D.), grant for Zhishan Lead Project of the Third Xiangya Hospital (H.D.), and grant for Hunan Provincial Innovation Foundation for Postgraduate, China (7138000008).

Conflict of Interest

The authors declare that they have no competing interests.

Open Access

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.


  1. 1.
    Narayanaswami P, Weiss M, Selcen D, David W, Raynor E, Carter G, Wicklund M, Barohn RJ et al (2014) Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 83:1453–1463CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Walton JN, Nattrass FJ (1954) On the classification, natural history and treatment of the myopathies. Brain 77:169–231CrossRefPubMedGoogle Scholar
  3. 3.
    Nigro V, Aurino S, Piluso G (2011) Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol 24:429–436CrossRefPubMedGoogle Scholar
  4. 4.
    Mahmood OA, Jiang XM (2014) Limb-girdle muscular dystrophies: where next after six decades from the first proposal (Review). Mol Med Rep 9:1515–1532PubMedPubMedCentralGoogle Scholar
  5. 5.
    Mitsuhashi S, Kang PB (2012) Update on the genetics of limb girdle muscular dystrophy. Semin Pediatr Neurol 19:211–218CrossRefPubMedGoogle Scholar
  6. 6.
    Takahashi T, Aoki M, Tateyama M, Kondo E, Mizuno T, Onodera Y, Takano R, Kawai H et al (2003) Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype. Neurology 60:1799–1804CrossRefPubMedGoogle Scholar
  7. 7.
    Zhang Y, Huang JJ, Wang ZQ, Wang N, Wu ZY (2012) Value of muscle enzyme measurement in evaluating different neuromuscular diseases. Clin Chim Acta 413:520–524CrossRefPubMedGoogle Scholar
  8. 8.
    Bushby KM (1995) Diagnostic criteria for the limb-girdle muscular dystrophies: report of the ENMC consortium on limb-girdle dystrophies. Neuromuscul Disord 5:71–74CrossRefPubMedGoogle Scholar
  9. 9.
    Bushby KM, Beckmann JS (1995) The limb-girdle muscular dystrophies—proposal for a new nomenclature. Neuromuscul Disord 5:337–343CrossRefPubMedGoogle Scholar
  10. 10.
    Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, Straub V, Robb S et al (2007) Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130:2725–2735CrossRefPubMedGoogle Scholar
  11. 11.
    Klinge L, Dean AF, Kress W, Dixon P, Charlton R, Muller JS, Anderson LV, Straub V et al (2008) Late onset in dysferlinopathy widens the clinical spectrum. Neuromuscul Disord 18:288–290CrossRefPubMedGoogle Scholar
  12. 12.
    Nigro V, Savarese M (2014) Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol 33:1–12PubMedPubMedCentralGoogle Scholar
  13. 13.
    Yuan L, Song Z, Xu H, Gu S, Zhu A, Gong L, Zhao Y, Deng H (2013) EIF4G1 Ala502Val and Arg1205His variants in Chinese patients with Parkinson disease. Neurosci Lett 543:69–71CrossRefPubMedGoogle Scholar
  14. 14.
    Yuan L, Wu S, Xu H, Xiao J, Yang Z, Xia H, Liu A, Hu P et al (2015) Identification of a novel PHEX mutation in a Chinese family with X-linked hypophosphatemic rickets using exome sequencing. Biol Chem 396:27–33CrossRefPubMedGoogle Scholar
  15. 15.
    Xiu X, Yuan J, Deng X, Xiao J, Xu H, Zeng Z, Guan L, Xu F et al (2014) A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing. Biomed Res Int 2014:186048PubMedPubMedCentralGoogle Scholar
  16. 16.
    Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C et al (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71:492–500CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C et al (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30:201–204CrossRefPubMedGoogle Scholar
  18. 18.
    Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A (1999) Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun 262:411–417CrossRefPubMedGoogle Scholar
  19. 19.
    Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al RM, Mukhtar MM, Urtizberea JA, Labeit S et al (2007) C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 61:340–351CrossRefPubMedGoogle Scholar
  20. 20.
    Nicolao P, Xiang F, Gunnarsson LG, Giometto B, Edstrom L, Anvret M, Zhang Z (1999) Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q. Am J Hum Genet 64:788–792CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Udd B, Kaarianen H, Somer H (1991) Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 14:1050–1058CrossRefPubMedGoogle Scholar
  22. 22.
    Udd B, Vihola A, Sarparanta J, Richard I, Hackman P (2005) Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64:636–642CrossRefPubMedGoogle Scholar
  23. 23.
    Penisson-Besnier I, Hackman P, Suominen T, Sarparanta J, Huovinen S, Richard-Cremieux I, Udd B (2010) Myopathies caused by homozygous titin mutations: limb-girdle muscular dystrophy 2J and variations of phenotype. J Neurol Neurosurg Psychiatry 81:1200–1202CrossRefPubMedGoogle Scholar
  24. 24.
    Labeit S, Kolmerer B (1995) Titins: giant proteins in charge of muscle ultrastructure and elasticity. Science 270:293–296CrossRefPubMedGoogle Scholar
  25. 25.
    Furst DO, Osborn M, Nave R, Weber K (1988) The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol 106:1563–1572CrossRefPubMedGoogle Scholar
  26. 26.
    Kotter S, Andresen C, Kruger M (2014) Titin: central player of hypertrophic signaling and sarcomeric protein quality control. Biol Chem 395:1341–1352CrossRefPubMedGoogle Scholar
  27. 27.
    Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D et al (2001) The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 89:1065–1072CrossRefPubMedGoogle Scholar
  28. 28.
    Kruger M, Linke WA (2011) The giant protein titin: a regulatory node that integrates myocyte signaling pathways. J Biol Chem 286:9905–9912CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sorimachi H, Freiburg A, Kolmerer B, Ishiura S, Stier G, Gregorio CC, Labeit D, Linke WA et al (1997) Tissue-specific expression and alpha-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs. J Mol Biol 270:688–695CrossRefPubMedGoogle Scholar
  30. 30.
    Fukuzawa A, Lange S, Holt M, Vihola A, Carmignac V, Ferreiro A, Udd B, Gautel M (2008) Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band: implications for hereditary myopathies. J Cell Sci 121:1841–1851CrossRefPubMedGoogle Scholar
  31. 31.
    Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B et al (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308:1599–1603CrossRefPubMedGoogle Scholar
  32. 32.
    Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N et al (2002) The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111:943–955CrossRefPubMedGoogle Scholar
  33. 33.
    Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS et al (2003) The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J Mol Biol 333:951–964CrossRefPubMedGoogle Scholar
  34. 34.
    Hauser MA, Conde CB, Kowaljow V, Zeppa G, Taratuto AL, Torian UM, Vance J, Pericak-Vance MA et al (2002) Myotilin mutation found in second pedigree with LGMD1A. Am J Hum Genet 71:1428–1432CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, Dancel R, Tim RW, Taivainen A et al (2000) Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 9:2141–2147CrossRefPubMedGoogle Scholar
  36. 36.
    Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R et al (2000) Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 24:163–166CrossRefPubMedGoogle Scholar
  37. 37.
    Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C et al (1995) Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A. Cell 81:27–40CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Wen Zheng
    • 1
    • 2
  • Han Chen
    • 1
  • Xiong Deng
    • 2
  • Lamei Yuan
    • 2
  • Yan Yang
    • 1
  • Zhi Song
    • 1
  • Zhijian Yang
    • 2
  • Yuan Wu
    • 2
    • 3
  • Hao Deng
    • 1
    • 2
  1. 1.Department of NeurologyThe Third Xiangya Hospital, Central South UniversityChangshaChina
  2. 2.Center for Experimental MedicineThe Third Xiangya Hospital, Central South UniversityChangshaChina
  3. 3.Department of Clinical LaboratoryThe Third Xiangya Hospital, Central South UniversityChangshaChina

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