title: Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin.
abstract: Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
authors.affiliation: Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
authors.forename: Monica
authors.initials: M
authors.lastname: Ohlsson
authors.forename: Carola
authors.initials: C
authors.lastname: Hedberg
authors.forename: Björn
authors.initials: B
authors.lastname: Brådvik
authors.forename: Christopher
authors.initials: C
authors.lastname: Lindberg
authors.forename: Homa
authors.initials: H
authors.lastname: Tajsharghi
authors.forename: Olof
authors.initials: O
authors.lastname: Danielsson
authors.forename: Atle
authors.initials: A
authors.lastname: Melberg
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D064211:Connectin; D005121:Extremities / Q000473:pathology; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000150:complications / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000150:complications / Q000235:genetics*; D013548:Sweden
chemical_list: D000199:Actins; D064211:Connectin; D009124:Muscle Proteins; D019006:Neural Cell Adhesion Molecules; C577285:TTN protein, human; D011494:Protein Kinases