A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy.
ABSTRACT Nemaline myopathies are diseases characterized by the presence in muscle fibres of pathognomonic rod bodies. These are composed largely of alpha-actinin and actin. We have identified a missense mutation in the alpha-tropomyosin gene, TPM3, which segregates completely with the disease in a family whose autosomal dominant nemaline myopathy we had previously localized to chromosome 1p13-q25. The mutation substitutes an arginine residue for a highly conserved methionine in a putative actin-binding site near the N terminus of the alpha-tropomyosin. The mutation may strengthen tropomyosin - actin binding, leading to rod body formation, by adding a further basic residue to the postulated actin-binding motif.
Full-textDOI: · Available from: Peter Blumbergs, Jun 26, 2014
SourceAvailable from: Gianina Ravenscroft[Show abstract] [Hide abstract]
ABSTRACT: The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.Brain 12/2014; DOI:10.1093/brain/awu368 · 10.23 Impact Factor
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ABSTRACT: Congenital myopathies are clinically and genetically heterogeneous disorders, which often remain genetically undiagnosed for many years. Here we present a 40-year old patient with an almost lifelong history of a congenital myopathy of unknown cause. Muscle biopsy in childhood revealed mild myopathic features and rods. Clinical examination on presentation at the age of 40 revealed a facial weakness, atrophy and weakness of the arm muscles and distal leg muscles with mild contractures of the foot flexors and the right elbow. Subsequently, the nebulin gene was identified as a putative candidate gene by linkage analyses, but sequence analysis only revealed one heterozygous splice site mutation in intron 73 (c.10872+1G>T). Therefore, "Next Generation Sequencing" was performed, which revealed a second pathogenic variant in exon 145 (c.21622A>C). Compound-heterozygous carrier status was confirmed via sequence analysis of the index patient's parents. Whole body muscle MRI showed a muscle involvement as previously described in nebulin-associated myopathies. Based on biopsy material, genetic analyses and muscle MRI, we identified two novel, compound-heterozygous variants in the nebulin gene after a 30 year clinical history, which cause a classical childhood type of nemaline myopathy. Copyright © 2015 Elsevier B.V. All rights reserved.Neuromuscular Disorders 02/2015; DOI:10.1016/j.nmd.2015.01.013 · 3.13 Impact Factor
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ABSTRACT: Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the 9 genes associated with the disease, 5 encode for components of striated muscle sarcomeres. In a genetic zebrafish screen the mutant träge (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganized and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of träge combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, while actin monomers polymerise to form thin filaments in skeletal muscle of tmod4(trg) mutants, thin filaments often appeared dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion, and early death. Myofibril of tmod4(trg) mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones, and electron-dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods together with the reactivity of rods with phalloidin and an antibody against actinin is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4(trg) mutants. While tropomodulin4 has not been associated with myopathy, the presented results make TMOD4 a novel candidate for unresolved nemaline myopathies and suggest the tmod4(trg) mutant as a valuable tool to study human muscle disorders.Disease Models and Mechanisms 10/2014; DOI:10.1242/dmm.017376 · 5.54 Impact Factor