Clinical and Myopathological Characteristics of Desminopathy Caused by a Mutation in Desmin Tail Domain

Maddison, Paul; Damian, Maxwell S.; Sewry, C.; McGorrian, Catherine; Winer, John; Odgerel, Zagaa; Shatunov, Aleksey; Lee, Hee Suk-U.-K.; Goldfarb, Lev G.

doi:10.1159/000341617

Cited by 11 publications

(8 citation statements)

References 40 publications

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“…Ando and colleagues demonstrated a helical right-handed twist of the homologous vimentin filaments (Ando et al 2004), which was previously also shown for desmin filaments by atomic force microscopy (Brodehl et al 2012a(Brodehl et al , 2016a. In addition, IFs can fuse end-to-end to elongate longitudinally (Colakoglu and Bar et al (2007), Maddison et al (2012) p.I451M 3 affected and 3 unaffected mutation carriers (Dalakas et al 2003) 0.00006598…”

Section: Cellular Functions Of Desminmentioning

confidence: 73%

Molecular insights into cardiomyopathies associated with desmin (DES) mutations

2018

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Increasing usage of next-generation sequencing techniques pushed during the last decade cardiogenetic diagnostics leading to the identification of a huge number of genetic variants in about 170 genes associated with cardiomyopathies, channelopathies, or syndromes with cardiac involvement. Because of the biochemical and cellular complexity, it is challenging to understand the clinical meaning or even the relevant pathomechanisms of the majority of genetic sequence variants. However, detailed knowledge about the associated molecular pathomechanism is essential for the development of efficient therapeutic strategies in future and genetic counseling. Mutations in DES, encoding the muscle-specific intermediate filament protein desmin, have been identified in different kinds of cardiac and skeletal myopathies. Here, we review the functions of desmin in health and disease with a focus on cardiomyopathies. In addition, we will summarize the genetic and clinical literature about DES mutations and will explain relevant cell and animal models. Moreover, we discuss upcoming perspectives and consequences of novel experimental approaches like genome editing technology, which might open a novel research field contributing to the development of efficient and mutation-specific treatment options.

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Section: Cellular Functions Of Desminmentioning

confidence: 73%

Molecular insights into cardiomyopathies associated with desmin (DES) mutations

2018

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“…Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alpha B‐crystallin [Clemen et al, ]. In contrast to previous findings, where the disorder causing mutations were located mainly to the central region of IF proteins, in desmin tail domain mutations were as well described [Maddison et al, ]. Desmin is involved in several types of cardiomyopathy, too.…”

Section: Involvement In Diseasementioning

confidence: 99%

Intrinsic Structural Disorder in Cytoskeletal Proteins

et al. 2013

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Cytoskeleton, the internal scaffold of the cell, displays an exceptional combination of stability and dynamics. It is composed of three major filamentous networks, microfilaments (actin filaments), intermediate filaments (neurofilaments), and microtubules. Together, they ensure the physical and structural stability of the cell, whereby also mediating its large-scale structural rearrangements, motility, stress response, division, and internal transport. All three cytoskeletal systems are built upon the same basic design: they have a central repetitive scaffold assembled from folded building elements, surrounded and regulated by accessory regions/proteins that regulate its formation and mediate its countless interactions with its environment, serving to send regulatory signals to and from the cytoskeleton. Here, we elaborate on the idea that the opposing features of stability and dynamics are also manifest in the dichotomy of the structural status of its components, the core being highly structured and the accessory proteins/regions being highly disordered, and are responsible for most of the regulatory (post-translational) input promoting adaptive responses and providing dynamics necessary for each of the cytoskeletal systems. This pattern entails special consequences, in which the manifold functional advantages of structural disorder, most pronounced in regulatory and signaling functions, are all exploited by nature. (MTs), and it provides the internal scaffold (skeleton) of the cell. It can be considered as a very special organelle, which represents a unique combination of stability and dynamics, physical rigidity and flexibility, long-time persistence and rapid, cataclysmic rearrangements. By providing a special microenvironment, the cytoskeleton ensures the physical separation of cellular constituents, thus segregating and directing cellular activities. It bridges molecular (nano-m) and cellular (micro-m) distances and represent the tracks of transport of cellular constituents over large distances. It provides the locomotive force of cell migration, it drives clustering of membrane proteins, drives cell division and the formation of protrusions the cell uses for exploring its environment. Apparently it does it by a combination of a physically rigid but inherently unstable central scaffold and a flexible and rather variable outer layer of accessory proteins/regions. Due to its central importance in cell physiology, the cytoskeleton is involved in many diseases, ranging from cancer to neurodegeneration [Pajkos et al., 2012;Raychaudhuri et al., 2009;Uversky et al., 2008]. Our central theme here is that multifaceted and highly dynamic behavior is enabled by structural disorder in all three major cytoskeletal constituents, also reflecting their increasing complexity from NFs to the actin cytoskeleton (Supporting Information Table S1, Table I). Intermediate filaments (IFs) have three principal components, IF-L(ight), IF-M(edium), and IF-H(igh), all three of which form an extended coiled-coil structures, from which...

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“…Nevertheless, such hypersensitivity reactions may not fully explain the pathogenesis of CLIPPERS. Furthermore, there is still no specific antineural surface antigen antibody that can be recognized [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Chronic hepatitis B infection presenting with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a case report

et al. 2015

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IntroductionChronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a brainstem disorder characterized by perivascular pathologic reaction with lymphocyte infiltration and leading to diplopia, facial palsy, dysarthria, and gait ataxia. It was thought to be an autoimmune disorder without distinct pathogenesis. Chronic hepatitis B virus infection has been proposed in correlation with autoimmune diseases, including central nervous system demyelinating disease. Patients with chronic hepatitis B infection may develop the syndrome of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.Case presentationA 34-year-old Taiwanese man who had been a hepatitis B virus carrier for a decade presented to our emergency room. He had influenza symptoms and progressive symptoms of left hemifacial numbness, double vision, and an unsteady gait of 2 days’ duration. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids was diagnosed, with increased hepatitis B viral load at the same time. He had no past history of similar neurologic deficits, and his liver function tests had been within normal limits before this episode. After corticosteroid and entecavir treatments, his neurological deficits and neuroimaging anomalies improved and his serum hepatitis B virus DNA viral load normalized.ConclusionsHepatitis B virus infection may induce central nervous system autoimmune reactions, including chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. In such cases, concomitant administration of corticosteroids and antiviral agent was helpful. We suggest further investigations in patients with regulatory T cell dysfunction, which may assist in clarifying a loss of immune tolerance in patients with such disorders.

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Clinical and Myopathological Characteristics of Desminopathy Caused by a Mutation in Desmin Tail Domain

Cited by 11 publications

References 40 publications

Molecular insights into cardiomyopathies associated with desmin (DES) mutations

Molecular insights into cardiomyopathies associated with desmin (DES) mutations

Intrinsic Structural Disorder in Cytoskeletal Proteins

Chronic hepatitis B infection presenting with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a case report

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