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Molecular Neurobiology

, Volume 54, Issue 9, pp 7212–7223 | Cite as

Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy

  • Anni Evilä
  • Johanna Palmio
  • Anna Vihola
  • Marco Savarese
  • Giorgio Tasca
  • Sini Penttilä
  • Sara Lehtinen
  • Per Harald Jonson
  • Jan De Bleecker
  • Peter Rainer
  • Michaela Auer-Grumbach
  • Jean Pouget
  • Emmanuelle Salort-Campana
  • Juan J. Vilchez
  • Nuria Muelas
  • Montse Olive
  • Peter Hackman
  • Bjarne Udd
Article

Abstract

Tibial muscular dystrophy (TMD) is the first described human titinopathy. It is a mild adult-onset slowly progressive myopathy causing weakness and atrophy in the anterior lower leg muscles. TMD is caused by mutations in the last two exons, Mex5 and Mex6, of the titin gene (TTN). The first reported TMD mutations were dominant, but the Finnish founder mutation FINmaj, an 11-bp insertion/deletion in Mex6, in homozygosity caused a completely different severe early-onset limb-girdle muscular dystrophy 2J (LGMD2J). Later, we reported that not all TMD mutations cause LGMD when homozygous or compound heterozygous with truncating mutation, but some of them rather cause a more severe TMD-like distal disease. We have now performed targeted next-generation sequencing of myopathy-related genes on seven families from Albania, Bosnia, Iran, Tunisia, Belgium, and Spain with juvenile or early adult onset recessive distal myopathy. Novel mutations in TTN Mex5, Mex6 and A-band exon 340 were identified in homozygosity or compound heterozygosity with a frameshift or nonsense mutation in TTN I- or A-band region. Family members having only one of these TTN mutations were healthy. Our results add yet another entity to the list of distal myopathies: juvenile or early adult onset recessive distal titinopathy.

Keywords

Distal myopathy Titinopathy Titin TTN 

Notes

Acknowledgments

This study was supported by the Folkhälsan Research Foundation, the Jane and Aatos Erkko Foundation, Association Française contre les Myopathies (SB/CP2013-0106, B.U.), the Academy of Finland (no. 138491, B.U.), the Sigrid Jusélius Foundation, the Liv och Hälsa Foundation, The Finnish Cultural Foundation (A.E.), Austrian Science Fund (FWF, P27634FW, M.A.), Tampere University Hospital Research Funds (B.U.), Fondo de Investigaciones Sanitarias—Instituto de Salud Carlos III (PI14-00738, M.O.), and the European Regional Development Fund (FEDER) (M.O.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2016_242_MOESM1_ESM.xlsx (15 kb)
Supplementary Table 1 (XLSX 14 kb)
12035_2016_242_MOESM2_ESM.xlsx (89 kb)
Supplementary Table 2 (XLSX 89 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anni Evilä
    • 1
  • Johanna Palmio
    • 2
  • Anna Vihola
    • 1
  • Marco Savarese
    • 1
    • 3
  • Giorgio Tasca
    • 4
    • 5
  • Sini Penttilä
    • 2
  • Sara Lehtinen
    • 2
  • Per Harald Jonson
    • 1
  • Jan De Bleecker
    • 6
  • Peter Rainer
    • 7
  • Michaela Auer-Grumbach
    • 8
  • Jean Pouget
    • 9
  • Emmanuelle Salort-Campana
    • 10
  • Juan J. Vilchez
    • 10
    • 11
  • Nuria Muelas
    • 10
    • 11
  • Montse Olive
    • 12
  • Peter Hackman
    • 1
  • Bjarne Udd
    • 1
    • 2
    • 13
  1. 1.Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman InstituteUniversity of HelsinkiHelsinkiFinland
  2. 2.Neuromuscular Research CenterUniversity of Tampere and Tampere University HospitalTampereFinland
  3. 3.Telethon Institute of Genetics and MedicinePozzuoliItaly
  4. 4.Institute of Neurology, Policlinico “A. Gemelli” Foundation University HospitalRomeItaly
  5. 5.Don Carlo Gnocchi ONLUS FoundationMilanItaly
  6. 6.Neuromuscular Reference Center and Neurology Department, Ghent University Hospital and St. Lucas General HospitalUniversity of GhentGhentBelgium
  7. 7.Division of CardiologyMedical University of GrazGrazAustria
  8. 8.Department of OrthopaedicsMedical University of ViennaViennaAustria
  9. 9.Neuromuscular and ALS Reference Center, La Timone HospitalAix-Marseille University, FILNEMUSMarseilleFrance
  10. 10.Department of NeurologyHospital Universitari i Politècnic La FeValenciaSpain
  11. 11.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)MadridSpain
  12. 12.Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of NeurologyIDIBELL-Hospital de Bellvitge, Hospitalet de LlobregatBarcelonaSpain
  13. 13.Neurology DepartmentVaasa Central HospitalVaasaFinland

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