G.O.2 Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin

Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
Brain (Impact Factor: 10.23). 05/2012; 135(Pt 6):1682-94. DOI: 10.1093/brain/aws103
Source: PubMed

ABSTRACT Hereditary myopathy with early respiratory failure (HMERF) and extensive myofibrillar lesions have been described in sporadic and familial cases and linked to various chromosomal regions. We describe the clinical manifestations, muscle histopathology and genetics in eight individuals from three apparently unrelated families with clinical and pathological features of HMERF. All patients had 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.274375, T>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 699 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry of this novel and first disease-causing mutation in A-band titin associated with HMERF.

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    • "Joint contractures leading to a contractile phenotype and a mild degree of calf hypertrophy are frequently observed [Carmignac et al., 2007; Ohlsson et al., 2012; Pfeffer et al., 2012; Ceyhan-Birsoy et al., 2013; Chauveau et al., 2014]. Abundant internal nuclei, multiminicores and other myofibrillar lesions (inclusions, marked Z-disc alterations, rimmed vacuoles), and fatty infiltration are common, although nonspecific histopathological findings [Carmignac et al., 2007; Ohlsson et al., 2012; Ceyhan-Birsoy et al., 2013; Chauveau et al., 2014; Evilä et al., 2014]. Secondary calpain3/p94 deficiency not due to CAPN3 mutations is often observed in muscles from TMD/LGMD2J, MmD-HD, and CNM patients with TTN mutations that alter the C-terminal calpain3/p94-binding domain [Carmignac et al., 2007; Hackman et al., 2008; Ceyhan-Birsoy et al., 2013; Evilä et al., 2014]. "
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    ABSTRACT: The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical and regulatory roles in cardiac and skeletal muscles. Prior to next generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to widespread use of NGS, TTN is emerging as a major gene in human inherited disease. So far, 127 TTN disease causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes or infantile diseases affecting both types of striated muscles. However, identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance and correlation with the phenotype of TTN sequence changes. In this review we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern and phenotype-genotype correlations, alongside with their implications for basic research and for human health. This article is protected by copyright. All rights reserved.
    Human Mutation 09/2014; 35(9). DOI:10.1002/humu.22611 · 5.05 Impact Factor
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    • "However, to date all families characterised with this mutation share common haplotypes, implying that all have inherited an ancestral allele: 8 UK-based families and one Canadian family (with British ancestry) share a single haplotype [3] [9]. All families with this mutation reported by Palmio and colleagues also share a common haplotype, which includes a British family (Family E) [8], and three previously reported Scandinavian families [1]. "
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    ABSTRACT: Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups.
    Neuromuscular Disorders 01/2013; 24(3). DOI:10.1016/j.nmd.2013.12.001 · 3.13 Impact Factor
  • Brain 05/2012; 135(Pt 6):1665-7. DOI:10.1093/brain/aws123 · 10.23 Impact Factor
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