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- Kostareva, Anna
(author)
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Genetic and pathophysiological study of desmin derangements in cardiac disorders
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Desmin is a chief intermediate filament of skeletal and cardiac muscle. Its main function is to provide structural and functional integrity to the cell and to transmit tension along the myofibrils, protecting them from mechanical stress during contractionrelaxation process. Desmin filaments encircle the Z-bands, link them to each other, to the nuclear membrane and to the cytoplasmic organelles, which make desmin filaments important for intracellular organelle positioning. Desmin has also been implicated in organisation and assembly of sarcomeres during myocyte development and in the process of signal transduction and apoptosis. Aberrations of cytoskeletal proteins and desmin in particular, have been implicated in the development of cardiomyopathies and myopathies. Desmin-related myopathies and cardiomyopathies constitute a heterogeneous group of severe, inherited disorders, which to various extent involve skeletal, cardiac and smooth muscles. The cardiac phenotype may include dilated, hypertrophic and restrictive cardiomyopathies, bundle branch block and A-V conduction block that result in severe heart failure, syncopal episodes and sudden death. Some of these patients need a permanent pacemaker implantation in early childhood. To identify the frequency of desmin mutation in patients with cardiomyopathies a direct sequencing of the desmin gene was performed. Two desmin mutations were identified in patients with dilated cardiomyopathy indicating that desmin gene derangements are not a common cause of cardiomyopathies. One of the described mutations was later proposed to be a rare polymorphism, raising a the question about the possible impact of structural gene polymorphism in the development of cardiac disorders. To elucidate pathophysiologial events underlying desmin cardiomyopathy and myopathy a transgenic mouse model carrying L345P desmin mutations was established using natural a desmin promoter. The desmin transgenic mice (DM) were characterized by moderate morphological alterations of cardiac muscle and cardiac hypertrophy as well as decrease of relative skeletal muscle force. The most striking feature of desmin transgenic mice were ultrastructural mitochondrial changes, namely severe swelling, vacuolization and crysta disruption. The mitochondrial Ca2+ level was significantly increased in cardiac and skeletal myocytes from DM mice compared to wild type, underlying the importance of desmin-mitochondrial interactions in the development of desmin cardiomyopathy\ myopathy. To assess the effects of various desmin mutations on the structural and functional properties of desmin filaments the desmin polymerization process was studied in vitro and in vivo. The study showed that different mutations of the desmin rod domain can compromise desmin polymerization at various stages and different amino acids are critically involved in distinct subunit interactions. However, some mutations do allow assembly to the filament state and still cause phenotype with aggregate formation in humans, suggesting that these mutations could affect interactions not relevant in in vitro conditions and in cultured cells but relevant for tissue homeostasis.
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- Kostareva, Anna, et al.
(author)
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Mice expressing L345P mutant desmin exhibit morphological and functional changes of skeletal and cardiac mitochondria
- 2008
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In: Journal of Muscle Research and Cell Motility. - : Springer Science and Business Media LLC. - 0142-4319 .- 1573-2657. ; 29:1, s. 25-36
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Journal article (peer-reviewed)abstract
- Desmin mutations underlie inherited myopathies/cardiomyopathies with varying severity and involvement of the skeletal and cardiac muscles. We developed a transgenic mouse model expressing low level of the L345P desmin mutation (DESMUT mice) in order to uncover changes in skeletal and cardiac muscles caused by this mutation. The most striking ultrastructural changes in muscle from DESMUT mice were mitochondrial swelling and vacuolization. The mitochondrial Ca2+ level was significantly increased in skeletal and cardiac myocytes from DESMUT mice compared to wild type cells during and after contractions. In isolated DESMUT soleus muscles, contractile function and recovery from fatigue were impaired. A SHIRPA screening test for neuromuscular performance demonstrated decreased motor function in DESMUT compared to WT mice. Echocardiographic changes in DESMUT mice included left ventricular wall hypertrophy and a decreased left ventricular chamber dimension. The results imply that low levels of L345P desmin acts, at least partially, by a dominant negative effect on mitochondria.
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- Martin, Alicia R, et al.
(author)
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Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland
- 2018
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 102:5, s. 760-775
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Journal article (peer-reviewed)abstract
- Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.
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