Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation

McNally, Elizabeth M.; Ly, Chantal T.; Rosenmann, Hanna; Mitrani-Rosenbaum, Stella; Jiang, Wei; Anderson, Louise V.B.; Soffer, Dov; Argov, Zohar

doi:10.1002/(sici)1096-8628(20000410)91:4<305::aid-ajmg12>3.0.co;2-s

Cited by 93 publications

(66 citation statements)

References 24 publications

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“…However, muscle inflammation that is dominated by a myeloid cell infiltrate is also a prominent feature of several, heritable, progressive muscle diseases, including Duchenne muscular dystrophy (DMD) (118), congenital muscular dystrophy (6,47), and limb girdle muscular dystrophy 2B (66,98). Although macrophages (123 129), mast cells (32), neutrophils (40), eosinophils (11,131), and cytotoxic T-lymphocytes (106) all contribute to pathogenesis in at least some of these chronic myopathic conditions, only macrophages and perhaps eosinophils are known to contribute to muscle regeneration.…”

Section: Do Immune Cells Regulate Muscle Repair and Regeneration In Csupporting

confidence: 88%

Regulatory interactions between muscle and the immune system during muscle regeneration

Tidball

Villalta

2010

American Journal of Physiology-Regulatory, Integrative and Comp

907

987

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Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298: R1173-R1187, 2010. First published March 10, 2010 doi:10.1152/ajpregu.00735.2009.-Recent discoveries reveal complex interactions between skeletal muscle and the immune system that regulate muscle regeneration. In this review, we evaluate evidence that indicates that the response of myeloid cells to muscle injury promotes muscle regeneration and growth. Acute perturbations of muscle activate a sequence of interactions between muscle and inflammatory cells. The initial inflammatory response is a characteristic Th1 inflammatory response, first dominated by neutrophils and subsequently by CD68 ϩ M1 macrophages. M1 macrophages can propagate the Th1 response by releasing proinflammatory cytokines and cause further tissue damage through the release of nitric oxide. Myeloid cells in the early Th1 response stimulate the proliferative phase of myogenesis through mechanisms mediated by TNF-␣ and IL-6; experimental prolongation of their presence is associated with delayed transition to the early differentiation stage of myogenesis. Subsequent invasion by CD163ϩ /CD206 ϩ M2 macrophages attenuates M1 populations through the release of anti-inflammatory cytokines, including IL-10. M2 macrophages play a major role in promoting growth and regeneration; their absence greatly slows muscle growth following injury or modified use and inhibits muscle differentiation and regeneration. Chronic muscle injury leads to profiles of macrophage invasion and function that differ from acute injuries. For example, mdx muscular dystrophy yields invasion of muscle by M1 macrophages, but their early invasion is accompanied by a subpopulation of M2a macrophages. M2a macrophages are IL-4 receptor ϩ /CD206 ϩ cells that reduce cytotoxicity of M1 macrophages. Subsequent invasion of dystrophic muscle by M2c macrophages is associated with progression of the regenerative phase in pathophysiology. Together, these findings show that transitions in macrophage phenotype are an essential component of muscle regeneration in vivo following acute or chronic muscle damage. skeletal muscle; macrophage; neutrophil; muscular dystrophy; chemokines SKELETAL MUSCLE HAS A REMARKABLE capacity for repair, even following severe damage. Experimental findings show that crushing muscle, killing muscle by the injection of toxins, mechanical destruction caused by large, lengthening stretches, or killing muscle fibers by freezing can be followed by the successful regeneration of muscle that leads to recovery of normal structure and function. The regenerative capacity of skeletal muscle relies largely on the presence of a population of mononucleated, myogenic cells, called satellite cells, that retain their ability to proliferate and then differentiate to either fuse with existing fibers or with other myogenic cells to generate new fibers. Thus, perturbations to the processes that normally regulate the activation, proliferat...

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Section: Do Immune Cells Regulate Muscle Repair and Regeneration In Csupporting

confidence: 88%

Regulatory interactions between muscle and the immune system during muscle regeneration

Tidball

Villalta

2010

American Journal of Physiology-Regulatory, Integrative and Comp

907

987

View full text Add to dashboard Cite

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“…This dysferlin/syntaxin-4 endocytic pathway may be relevant to studies of known syntaxin-4-dependent cargo; syntaxin-4 is involved in the trafficking of GLUT4 receptors in response to insulin (33)(34)(35), and has also been associated with cytokine release in macrophages (36). This inflammatory association is particularly interesting given the marked inflammatory response in dysferlinopathy (37) and the abnormal immune signaling in the dysferlin-deficient mouse (38 -41). Of note, the dysferlin/syntaxin-4 endosomal association is maintained even when dysferlin is severely truncated (C2F-TM).…”

Section: Discussionmentioning

confidence: 99%

Reduced Plasma Membrane Expression of Dysferlin Mutants Is Attributed to Accelerated Endocytosis via a Syntaxin-4-associated Pathway

Evesson

Peat

Lek

et al. 2010

Journal of Biological Chemistry

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Ferlins are an ancient family of C2 domain-containing proteins, with emerging roles in vesicular trafficking and human disease. Dysferlin mutations cause inherited muscular dystrophy, and dysferlin also shows abnormal plasma membrane expression in other forms of muscular dystrophy. We establish dysferlin as a shortlived (protein half-life ϳ4 -6 h) and transitory transmembrane protein (plasma membrane half-life ϳ3 h), with a propensity for rapid endocytosis when mutated, and an association with a syntaxin-4 endocytic route. Dysferlin plasma membrane expression and endocytic rate is regulated by the C2B-FerI-C2C motif, with a critical role identified for C2C. Disruption of C2C dramatically reduces plasma membrane dysferlin (by 2.5-fold), due largely to accelerated endocytosis (by 2.5-fold). These properties of reduced efficiency of plasma membrane expression due to accelerated endocytosis are also a feature of patient missense mutant L344P (within FerI, adjacent to C2C). Importantly, dysferlin mutants that demonstrate accelerated endocytosis also display increased protein lability via endosomal proteolysis, implicating endosomal-mediated proteolytic degradation as a novel basis for dysferlin-deficiency in patients with single missense mutations. Vesicular labeling studies establish that dysferlin mutants rapidly transit from EEA1-positive early endosomes through to dextran-positive lysosomes, co-labeled by syntaxin-4 at multiple stages of endosomal transit. In summary, our studies define a transient biology for dysferlin, relevant to emerging patient therapeutics targeting dysferlin replacement. We introduce accelerated endosomal-directed degradation as a basis for lability of dysferlin missense mutants in dysferlinopathy, and show that dysferlin and syntaxin-4 similarly transit a common endosomal pathway in skeletal muscle cells.

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“…This inflammation is of uncertain significance. Perivascular mononuclear cell inflammation is a frequent finding in some hereditary neuromuscular disorders, including fascioscapulohumeral dystrophy 32 and the dysferlinopathies, 33 but to our knowledge, has not been reported for any SMA. Additional pathologic studies are needed to clarify whether inflammation is a consistent finding in SMA-LED.…”

Section: Clinical Featuresmentioning

confidence: 99%

Dominant spinal muscular atrophy with lower extremity predominance

et al. 2010

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Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA.Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed.Results: Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 ( ϭ 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,368,585. No segregating copy number variations were found within the disease interval. Conclusions:We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant. Neurology Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of spinal cord motor neurons. The majority of SMA cases show autosomal recessive inheritance and are caused by homozygous deletion or mutation of the SMN1 gene on 5q (OMIM 253300, 253550, 253400, and 271150). Non-5q SMAs are rare, clinically diverse, and genetically heterogeneous.1,2 They are commonly classified by inheritance pattern and whether weakness involves predominantly distal or proximal musculature.The non-5q SMAs with distal-predominant weakness show phenotypic overlap with the distal hereditary motor neuropathies. Recessive disorders in this category are caused by mutations in IGHMBP2, 3 PLEKHG5, 4 or show linkage to 9p21.1-p12 5 or 11q.13. 6 Dominant

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Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation

Cited by 93 publications

References 24 publications

Regulatory interactions between muscle and the immune system during muscle regeneration

Regulatory interactions between muscle and the immune system during muscle regeneration

Reduced Plasma Membrane Expression of Dysferlin Mutants Is Attributed to Accelerated Endocytosis via a Syntaxin-4-associated Pathway

Dominant spinal muscular atrophy with lower extremity predominance

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