Dysferlin expression in monocytes: A source of mRNA for mutation analysis

Luna, Noemí de; Freixas, Alba; Gallano, P.; Caselles, Lidia; Rojas‐García, Ricardo; Paradas, Carmen; Nogales‐Gadea, Gisela; Domínguez‐Perles, Raúl; Gonzalez‐Quereda, Lidia; Vílchez, Juan J.; Márquez, Cristina; Bautista, Juan; Guerrero, Antonio José Moreno; Salazar, Jason; Pou, Adolf; Illa, Isabel; Gallardo, Eduard

doi:10.1016/j.nmd.2006.09.006

Cited by 74 publications

(62 citation statements)

References 25 publications

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“…This wide spectrum of identified DYSF mutations increases the difficulty of finding feasible treatments for these diseases. While the exon skipping technique has opened interesting new avenues for DMD treatment [14,16,17,45], it has been clearly demonstrated that several dysferlin exons could not be skipped as their suppression would be undoubtedly deleterious [46,47]. Surprisingly, in 2006, Sinnreich et al reported a positive genotype-phenotype correlation in an LGMD-2B family with two severely affected sisters and a mildly affected mother.…”

Section: Discussionmentioning

confidence: 99%

Full‐length dysferlin expression driven by engineered human dystrophic blood derived CD133+ stem cells

et al. 2013

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The protein dysferlin is abundantly expressed in skeletal and cardiac muscles, where its main function is membrane repair. Mutations in the dysferlin gene are involved in two autosomal recessive muscular dystrophies: Miyoshi myopathy and limb‐girdle muscular dystrophy type 2B. Development of effective therapies remains a great challenge. Strategies to repair the dysferlin gene by skipping mutated exons, using antisense oligonucleotides (AONs), may be suitable only for a subset of mutations, while cell and gene therapy can be extended to all mutations. AON‐treated blood‐derived CD133+ stem cells isolated from patients with Miyoshi myopathy led to partial dysferlin reconstitution in vitro but failed to express dysferlin after intramuscular transplantation into scid/blAJ dysferlin null mice. We thus extended these experiments producing the full‐length dysferlin mediated by a lentiviral vector in blood‐derived CD133+ stem cells isolated from the same patients. Transplantation of engineered blood‐derived CD133+ stem cells into scid/blAJ mice resulted in sufficient dysferlin expression to correct functional deficits in skeletal muscle membrane repair. Our data suggest for the first time that lentivirus‐mediated delivery of full‐length dysferlin in stem cells isolated from Miyoshi myopathy patients could represent an alternative therapeutic approach for treatment of dysferlinopathies.

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Section: Discussionmentioning

confidence: 99%

Full‐length dysferlin expression driven by engineered human dystrophic blood derived CD133+ stem cells

et al. 2013

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“…Dysferlinopathies have also been shown to be associated with a late-onset dilative cardiomyopathy (4)(5)(6). Dysferlin is a 230-kDa protein that is widely expressed in different tissues and cells including striated muscle (7) and immune cells (8)(9)(10). Previous work using dysferlin mutant mice demonstrated that dysferlin plays an essential role in cell membrane repair of striated muscle (5,(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

Han¹,

Frett²,

Levy³

et al. 2010

J. Clin. Invest.

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Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood. Although muscle inflammation is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution of the immune system to the pathology of dysferlinopathy remains to be fully explored. Here, we show that the complement system plays an important role in muscle pathology in dysferlinopathy. Dysferlin deficiency led to increased expression of complement factors in muscle, while muscle-specific transgenic expression of dysferlin normalized the expression of complement factors and eliminated the dystrophic phenotype present in dysferlin-null mice. Furthermore, genetic disruption of the central component (C3) of the complement system ameliorated muscle pathology in dysferlin-deficient mice but had no significant beneficial effect in a genetically distinct model of muscular dystrophy, mdx mice. These results demonstrate that complement-mediated muscle injury is central to the pathogenesis of dysferlinopathy and suggest that targeting the complement system might serve as a therapeutic approach for this disease.

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“…11,13,14 Normal monocytes contain dysferlin, and LGMD2B/MM patients lack dysferlin in their monocytes. 16,17 We have recently shown that dysferlin-deficient monocytes display abnormal signaling and phagocytotic activity that could contribute to excessive inflammation in patient muscle. 18 Further, human LGMD2B and mouse (SJL) dysferlin-deficient muscle showed macrophage and dendritic cell activation markers, including HLA-DR, HLA-ABC, and CD86 (human), and MOMA-2, CD11c, and ICAM-1 (mice) suggesting that mild myofiber damage in dysferlin-deficient muscle may result in an exaggerated monocyte/dendritic cell response secondary to dysferlin protein loss.…”

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confidence: 99%

Dysferlin Deficiency Shows Compensatory Induction of Rab27A/Slp2a That May Contribute to Inflammatory Onset

Kesari

Fukuda

Knoblach

et al. 2008

The American Journal of Pathology

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Mutations in the dysferlin gene cause limb girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy. Dysferlin-deficient cells show abnormalities in vesicular traffic and membrane repair although onset of symptoms is not commonly seen until the late teenage years and is often associated with subacute onset and marked muscle inflammation. To identify molecular networks specific to dysferlin-deficient muscle that might explain disease pathogenesis, muscle mRNA profiles from 10 mutation-positive LGMD2B/MM patients were compared with a disease control [LGMD2I; (n ‫؍‬ 9)], and normal muscle samples (n ‫؍‬ 11). Query of inflammatory pathways suggested LGMD2B-specific increases in co-stimulatory signaling between dendritic cells and T cells (CD86, CD28, and CTLA4), associated with localized expression of both versican and tenascin. LGMD2B muscle also showed an increase in vesicular trafficking pathway proteins not normally observed in muscle (synaptotagmin-like protein Slp2a/SYTL2 and the small GTPase Rab27A). We propose that Rab27A/Slp2a expression in LGMD2B muscle provides a compensatory vesicular trafficking pathway that is able to repair membrane damage in the absence of dysferlin. However, this same pathway may release endocytotic vesicle contents, resulting in an inflammatory microenvironment. As dysferlin deficiency has been shown to enhance phagocytosis by macrophages, together with our findings of abnormal myofiber endocytosis pathways and dendritic-T cell activation markers, these results suggest a model of immune and inflammatory network over-stimulation that may explain the subacute inflammatory presentation. Limb-girdle muscular dystrophies are a group of heterogeneous disorders typically showing an autosomal recessive mode of inheritance, progressive muscle weakness, and high serum creatine kinase levels.1 Two types of muscle disease, a distal myopathy (Miyoshi Myopathy, MM) and a form of limb girdle muscular dystrophy (LGMD2B) have both been shown to be caused by mutations of the dysferlin gene. 2,3 In both LGMD2B and MM, dysferlin gene mutations result in partial or complete loss of dysferlin protein in muscle as measured by immunoassays, although the reduction in dysferlin levels does not strictly correlate with clinical severity. 4 Both the proximal (LGMD2B) and distal (MM) phenotypes can be caused by identical mutations in the same family, suggesting the role of genetic modifiers and/or environmental influence on disease expression. 5 The dysferlin gene is localized to 2p13 with expression in various tissues ranging from kidney to monocytes, with highest levels in skeletal and cardiac muscle.6 Dysferlin is localized predominantly to the muscle surface membrane, and is also associated with cytoplasmic vesicles. 7The dysferlin protein was originally named based on its similarity to the Caenorhabditis elegans protein FER-1. FER-1 is responsible for mediating fusion of intracellular vesicles with the spermatid plasma membrane.8 Sequence homology between FER-1 and dysferlin includes Supplemental materia...

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Dysferlin expression in monocytes: A source of mRNA for mutation analysis

Cited by 74 publications

References 25 publications

Full‐length dysferlin expression driven by engineered human dystrophic blood derived CD133+ stem cells

Full‐length dysferlin expression driven by engineered human dystrophic blood derived CD133+ stem cells

Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice

Dysferlin Deficiency Shows Compensatory Induction of Rab27A/Slp2a That May Contribute to Inflammatory Onset

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