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.
"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]. "
[Show abstract][Hide abstract] 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 · 5.14 Impact Factor
"The data also highlight the possible involvement of novel loci and molecular pathways in SAD, the most enriched of which are neurotransmission and synaptic function, neurodegeneration and neural diseases, ER- Golgi protein trafficking and transport, extracellular matrix/adhesion, DNA/RNA metabolism, repair and genomic instability (Table 4). Moreover, several of the identified loci encode for proteins with important functions in muscular physiology which are responsible for inherited neuromuscular disorders and dystrophies (e.g., DYSF, MYH13, NEB, OBSCN, and SYNE1)       . Some of these muscular proteins are highly expressed in brain, including amyloid deposits , and their mutations cause severe synaptic and neurological deficits   . "
[Show abstract][Hide abstract] ABSTRACT: Background: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. Objective: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. Methods: By using bioinfiormatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. Results: We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. Conclusion: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.
"Recent evidence of mutations outside of the kinase domain can also cause this same disease. These findings suggest that the molecular mechanism of kinase stretch activation is more complicated than first suspected, and may involve multiple other sites within titin (Ohlsson et al., 2012; Pfeffer et al., 2012). A more extensive review of the kinase domain can be found in Kontrogianni-Konstantopoulos et al. (2009); Gautel (2011a); Temmerman et al. (2013). "
[Show abstract][Hide abstract] ABSTRACT: Giant muscle proteins (e.g., titin, nebulin, and obscurin) play a seminal role in muscle elasticity, stretch response, and sarcomeric organization. Each giant protein consists of multiple tandem structural domains, usually arranged in a modular fashion spanning 500 kDa to 4 MDa. Although many of the domains are similar in structure, subtle differences create a unique function of each domain. Recent high and low resolution structural and dynamic studies now suggest more nuanced overall protein structures than previously realized. These findings show that atomic structure, interactions between tandem domains, and intrasarcomeric environment all influence the shape, motion, and therefore function of giant proteins. In this article we will review the current understanding of titin, obscurin, and nebulin structure, from the atomic level through the molecular level.
Frontiers in Physiology 12/2013; 4:368. DOI:10.3389/fphys.2013.00368 · 3.53 Impact Factor
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