title: Targeted Next-Generation Sequencing Reveals Novel TTN Mutations Causing Recessive Distal Titinopathy.
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.
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland. anni.evila@helsinki.fi.
authors: Anni
authors: A
authors: Evilä
authors: Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors: Johanna
authors: J
authors: Palmio
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors: Anna
authors: A
authors: Vihola
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.|Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
authors: Marco
authors: M
authors: Savarese
authors: Institute of Neurology, Policlinico "A. Gemelli" Foundation University Hospital, Rome, Italy.|Don Carlo Gnocchi ONLUS Foundation, Milan, Italy.
authors: Giorgio
authors: G
authors: Tasca
authors: Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors: Sini
authors: S
authors: Penttilä
authors: Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors: Sara
authors: S
authors: Lehtinen
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors: Per Harald
authors: PH
authors: Jonson
authors: Neuromuscular Reference Center and Neurology Department, Ghent University Hospital and St. Lucas General Hospital, University of Ghent, Ghent, Belgium.
authors: Jan
authors: J
authors: De Bleecker
authors: Division of Cardiology, Medical University of Graz, Graz, Austria.
authors: Peter
authors: P
authors: Rainer
authors: Department of Orthopaedics, Medical University of Vienna, Vienna, Austria.
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: Neuromuscular and ALS Reference Center, La Timone Hospital, Aix-Marseille University, FILNEMUS, Marseille, France.
authors: Jean
authors: J
authors: Pouget
authors: Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.
authors: Emmanuelle
authors: E
authors: Salort-Campana
authors: Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors: Juan J
authors: JJ
authors: Vilchez
authors: Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors: Nuria
authors: N
authors: Muelas
authors: Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors: Montse
authors: M
authors: Olive
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors: Peter
authors: P
authors: Hackman
authors: Folkhälsan Institute of Genetics, Biomedicum Helsinki and Department of Medical Genetics, Haartman Institute, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.|Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, Finland.|Neurology Department, Vaasa Central Hospital, Vaasa, Finland.
authors: Bjarne
authors: B
authors: Udd
mesh_terms: D064211:Connectin / Q000235:genetics*; D049310:Distal Myopathies / Q000000981:diagnostic imaging* / Q000235:genetics*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*; D055815:Young Adult
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: Distal myopathy; TTN; Titin; Titinopathy