Browsing by Subject "MYOPATHY"

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  • Harris, Elizabeth; Töpf, Ana; Vihola, Anna; Evilä, Anni; Barresi, Rita; Hudson, Judith; Hackman, Peter; Herron, Brian; MacArthur, Daniel; Lochmüller, Hanns; Bushby, Kate; Udd, Bjarne; Straub, Volker (2017)
    Mutations in the gene encoding the giant skeletal muscle protein titin are associated with a variety of muscle disorders, including recessive congenital myopathies cardiomyopathy, limb girdle muscular dystrophy (LGMD) and late onset dominant distal myopathy. Heterozygous truncating mutations have also been linked to dilated cardiomyopathy. The phenotypic spectrum of titinopathies is emerging and expanding, as next generation sequencing techniques make this large gene amenable to sequencing. We undertook whole exome sequencing in four individuals with LGMD. An essential splice site mutation, previously reported in dilated cardiomyopathy, was identified in all families in combination with a second truncating mutation. Affected individuals presented with childhood onset proximal weakness associated with joint contractures and elevated CK. Cardiac dysfunction was present in two individuals. Muscle biopsy showed increased internal nuclei and immunoblotting identified reduction or absence of calpain-3 and demonstrated a marked reduction of C-terminal titin fragments. We confirm the co-occurrence of cardiac and skeletal myopathies associated with recessive truncating titin mutations. Compound heterozygosity of a truncating mutation previously associated with dilated cardiomyopathy and a 'second truncation' in TTN was identified as causative in our skeletal myopathy patients. These findings add to the complexity of interpretation and genetic counselling for titin mutations. (C) 2017 Elsevier B.V. All rights reserved.
  • Boczkowska, Malgorzata; Rebowski, Grzegorz; Kremneva, Elena; Lappalainen, Pekka; Dominguez, Roberto (2015)
    How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) are prototypical actin filament pointed-end-capping proteins, whereas their homologues, Leiomodins (Lmods), are powerful filament nucleators. We show that Tmods and Lmods do not compete biochemically, and display similar but distinct localization in sarcomeres. Changes along the polypeptide chains of Tmods and Lmods exquisitely adapt their functions for capping versus nucleation. Tmods have alternating tropomyosin (TM)- and actin-binding sites (TMBS1, ABS1, TMBS2 and ABS2). Lmods additionally contain a C-terminal extension featuring an actin-binding WH2 domain. Unexpectedly, the different activities of Tmods and Lmods do not arise from the Lmodspecific extension. Instead, nucleation by Lmods depends on two major adaptations-the loss of pointed-end-capping elements present in Tmods and the specialization of the highly conserved ABS2 for recruitment of two or more actin subunits. The WH2 domain plays only an auxiliary role in nucleation.
  • Khan, Sofia; Ince-Dunn, Gulayse; Suomalainen, Anu; Elo, Laura L. (2020)
    High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.
  • Buzkova, Jana; Nikkanen, Joni; Ahola, Sofia; Hakonen, Anna H.; Sevastianova, Ksenia; Hovinen, Topi; Yki-Järvinen, Hannele; Pietiläinen, Kirsi H.; Lönnqvist, Tuula; Velagapudi, Vidya; Carroll, Christopher J.; Suomalainen, Anu (2018)
    Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We investigated metabolomes of 25 mitochondrial myopathy or ataxias patients, 16 unaffected carriers, six IBM and 15 non-mitochondrial neuromuscular disease (NMD) patients and 30 matched controls. MD and IBM metabolomes clustered separately from controls and NMDs. MDs and IBM showed transsulfuration pathway changes; creatine and niacinamide depletion marked NMDs, IBM and infantile-onset spinocerebellar ataxia (IOSCA). Low blood and muscle arginine was specific for patients with m.3243A>G mutation. A four-metabolite blood multi-biomarker (sorbitol, alanine, myoinositol, cystathionine) distinguished primary MDs from others (76% sensitivity, 95% specificity). Our omics approach identified pathways currently used to treat NMDs and mitochondrial stroke-like episodes and proposes nicotinamide riboside in MDs and IBM, and creatine in IOSCA and IBM as novel treatment targets. The disease-specific metabolic fingerprints are valuable "multi-biomarkers" for diagnosis and promising tools for follow-up of disease progression and treatment effect.
  • Suomalainen, Anu (2015)
    This commentary inaugurates a new review series in EMBO Molecular Medicine focused on mitochondrial diseases. This area of medicine, which actually encompasses most disease areas, has long since come of age and is now positioned for the next leap toward the development of effective therapies. The aims of the review series are to offer a comprehensive overview of this exciting area of medicine and research and to provide timely discussions for clinicians and investigators on the new discoveries elucidating how mitochondrial metabolism contributes to an expanding group of complex, heterogeneous, and difficult-to-tackle diseases.
  • Palmio, Johanna; Jonson, Per Harald; Evilä, Anni; Auranen, Mari; Straub, Volker; Bushby, Kate; Sarkozy, Anna; Kiuru-Enari, Sari; Sandell, Satu; Pihko, Helena; Hackman, Peter; Udd, Bjarne (2015)
    DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation. (C) 2015 Elsevier B.V. All rights reserved.
  • Soglia, Francesca; Petracci, Massimiliano; Puolanne, Eero (2020)
    The present study aims to measure the sarcomere lengths in normal broiler muscles and in non-lesion sites of breast muscles focally affected by Wooden Breast (WB). For this purpose, twenty Pectoralis major muscles (10 unaffected and 10 WB-focally affected cases) were sampled and used to measure sarcomere length by laser diffraction method. When compared with their unaffected counterpart, WB cases exhibited 13% longer sarcomeres (1.91 vs. 1.69 mu m; p <.001) measured within the non-lesioned site of the muscle. Although it is not simple to draw conclusions about the lesion properties based on the non-lesion area, but as the fibres are bound to each other, it may be reasonable to anticipate that the hardened consistency observed in WB is not ascribable to a more intense contraction of the sarcomeres. In addition, considering the current knowledge concerning this condition, it might be assumed that the longer sarcomeres observed in WB are not triggering the development of this condition but are rather a consequence of the profound alteration in the muscular structure resulting from it. Indeed, despite the outstanding improvements in the live and slaughtering traits, the selection programmes carried out in the past years have resulted in a reduced capillarization and impaired oxygen supply to the Pectoralis major of fast-growing hybrids thus affecting the physiology of its constituting fibres as well as maybe impairing their ability to synthetise new sarcomeres. This may result in a skeletal muscle injury, which would ultimately lead to necrosis and fibrosis.
  • Evila, Anni; Palmio, Johanna; Vihola, Anna; Savarese, Marco; Tasca, Giorgio; Penttila, Sini; Lehtinen, Sara; Jonson, Per Harald; De Bleecker, Jan; Rainer, Peter; Auer-Grumbach, Michaela; Pouget, Jean; Salort-Campana, Emmanuelle; Vilchez, Juan J.; Muelas, Nuria; Olive, Montse; Hackman, Peter; Udd, Bjarne (2017)
    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.