| 1. |
- Dahl-Halvarsson, Martin, et al.
(author)
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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
- 2018
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:28
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Journal article (peer-reviewed)abstract
- Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/beta-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the alpha-helical rod domain of MYH7 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.
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| 2. |
- Dahl-Halvarsson, Martin, et al.
(author)
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Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase
- 2020
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In: Disease Models & Mechanisms. - : The Company of Biologists. - 1754-8403 .- 1754-8411. ; 13:12
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Journal article (peer-reviewed)abstract
- Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/beta-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases of myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of the R1845W mutation. This study shows that a higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was suppressed by expression of Thin (herein referred to as Abba), an E3 ubiquitin ligase. This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities, including extensive loss of thick filaments with selective A-band loss, and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Furthermore, the impaired muscle morphology associated with the mutant allele was suppressed by expression of Abba. These findings suggest that modification of the ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.
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| 3. |
- Dahl-Halvarsson, Martin, et al.
(author)
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Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells
- 2017
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Journal article (peer-reviewed)abstract
- Myosin storage myopathy is a protein aggregate myopathy associated with the characteristic subsarcolemmal accumulation of myosin heavy chain in muscle fibers. Despite similar histological findings, the clinical severity and age of onset are highly variable, ranging from no weakness to severe impairment of ambulation, and usually childhood-onset to onset later in life. Mutations located in the distal end of the tail of slow/beta-cardiac myosin heavy chain are associated with myosin storage myopathy. Four missense mutations (L1793P, R1845W, E1883K and H1901L), two of which have been reported in several unrelated families, are located within or closed to the assembly competence domain. This location is critical for the proper assembly of sarcomeric myosin rod filaments. To assess the mechanisms leading to protein aggregation in myosin storage myopathy and to evaluate the impact of these mutations on myosin assembly and muscle function, we expressed mutated myosin proteins in cultured human muscle cells and in the nematode Caenorhabditis elegans. While L1793P mutant myosin protein efficiently incorporated into the sarcomeric thick filaments, R1845W and H1901L mutants were prone to formation of myosin aggregates without assembly into striated sarcomeric thick filaments in cultured muscle cells. In C. elegans, mutant alleles of the myosin heavy chain gene unc-54 corresponding to R1845W, E1883K and H1901L, were as effective as the wild-type myosin gene in rescuing the null mutant worms, indicating that they retain functionality. Taken together, our results suggest that the basis for the pathogenic effect of the R1845W and H1901L mutations are primarily structural rather than functional. Further analyses are needed to identify the primary trigger for the histological changes seen in muscle biopsies of patients with L1793P and E1883K mutations.
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| 4. |
- Dahl-Halvarsson, Martin
(author)
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Study the role of patient-specific mutations by genetic disease modeling : From gene to function; A study to understand muscles
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Many genetic diseases inherited in a dominant fashion have a complex pathological pattern. TOR1A mediated Dystonia-1 (DYT1) is an example of incomplete penetrance, affecting only a third of the carriers. DYT1 is an early-onset neurological disease affecting dopamine release from substantia nigra to the striatum in the brain, causing muscle tremors in muscles. We have identified the first cases of homozygous TOR1A mutation together with a new TOR1A mutation all of them showing DYT1 symptoms from birth. The main part of this thesis has gone to describing the skeletal myosin myopathies Laing early-onset myopathy (MPD1) and myosin storage myopathy (MSM). The diseases are known for causing slow progressive muscle atrophy with huge variations on progression rate. Individuals within the same family can exhibit wildly different speed of atrophy. We show with cell assays that various MYH7, which all leads to myosin storage myopathy, are caused by different mechanisms. We also show that Drosophila melanogaster, fruit flies, carrying MPD1 and MSM mutations becomes resilient when overexpressing the enzymatic ubiquitin E3-ligase TRIM32. The enzyme is a homolog to the human MuRF enzyme, known to mediate myosin breakdown. Lastly we have found a family where a mutation in the myosin folding chaperone UNC-45B drives the heart condition hypertrophic cardiomyopathy. UNC-45B have been shown to be important for embryonic heart development but never been found to be associated with any muscle disease before.
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| 5. |
- Kariminejad, A., et al.
(author)
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TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor
- 2017
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 140:11, s. 2851-2859
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Journal article (peer-reviewed)abstract
- Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.
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