Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B

Bittner, Reginald E.; Anderson, Louise V.B.; Burkhardt, Elke; Bashir, Rumaisa; Vafiadaki, Elizabeth; Ivanova, Silva; Raffelsberger, Thomas; Maerk, I; Höger, Harald; Jung, Martin; Karbasiyan, Mohsen; Storch, Maria K.; Lassmann, Hans; Moss, Jennifer A.; Davison, Kenneth; Harrison, Roger W.; Bushby, Kate; Reis, André

doi:10.1038/13770

Cited by 190 publications

(153 citation statements)

References 11 publications

(7 reference statements)

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“…When suspended from the tail, CAR ϩ/ϩ mice ( Figure 1B) invariably kept their hindlimbs adducted, a behavior recapitulated in other murine models of muscle disease such as the dystrophin-and dysferlin-deficient mice. 29,30 This is in marked contrast to the reflex of normal mice ( Figure 1A) that extend and outstretch the hindlimbs on suspension.…”

Section: Gross Appearance Of Car Homozygous Transgenic Mice (Carmentioning

confidence: 48%

“…Although it is presently unclear how persistent overexpression of CAR brings about such dramatic changes in the accumulation of dystrophin, dysferlin, caveolin-3, and ␤-dystroglycan in mature skeletal muscle, our observations are consistent with the more severe pathological phenotype and shortened lifespan of the CAR homozygotes in comparison with either mdx, caveolin-3-overexpressing, 12 or dysferlin-null mice. 20,29 Although the transgenic CAR model does not have a human counterpart, it provides a valuable example of possible interactions of clinically important molecules of the muscle cell surface.…”

Section: Relation To Human and Mouse Myopathiesmentioning

confidence: 99%

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Simultaneous Dystrophin and Dysferlin Deficiencies Associated with High-Level Expression of the Coxsackie and Adenovirus Receptor in Transgenic Mice

Shaw

Larochelle

Dudley

et al. 2006

The American Journal of Pathology

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The Coxsackie and adenovirus receptor (CAR) , a cell adhesion molecule of the immunoglobulin superfamily , is usually confined to the sarcolemma at the neuromuscular junction in mature skeletal muscle fibers. Previously , we reported that adenovirusmediated gene transfer is greatly facilitated in hemizygous transgenic mice with extrasynaptic CAR expression driven by a muscle-specific promoter. However , in the present study , when these mice were bred to homozygosity , they developed a severe myopathic phenotype and died prematurely. Large numbers of necrotic and regenerating fibers were present in the skeletal muscle of the homozygous CAR transgenics. The myopathy was further characterized by increased levels of caveolin-3 and ␤-dystroglycan and decreased levels of dystrophin , dysferlin , and neuronal nitric-oxide synthase. Even the hemizygotes manifested a subtle phenotype , displaying deficits in isometric force generation and perturbed mitogen-activated protein kinase (MAPK-erk1/2) activation during contraction. There are few naturally occurring or engineered mouse lines showing as severe a skeletal myopathy as observed with ectopic expression of CAR in the homozygotes. Taken together , these findings suggest that substantial overexpression of CAR may lead to physiological dysfunction by disturbing sarcolemmal integrity (through dystrophin deficiency) , impairing sarcolemmal repair (through dysferlin deficiency) , and interfering with normal signaling (through alterations in caveolin-3 and neuronal nitric-oxide synthase levels). (Am J Pathol

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Section: Gross Appearance Of Car Homozygous Transgenic Mice (Carmentioning

confidence: 48%

Section: Relation To Human and Mouse Myopathiesmentioning

confidence: 99%

Simultaneous Dystrophin and Dysferlin Deficiencies Associated with High-Level Expression of the Coxsackie and Adenovirus Receptor in Transgenic Mice

Shaw

Larochelle

Dudley

et al. 2006

The American Journal of Pathology

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“…Although no background dysferlin staining was detected from our uninjected sjl animals ( Fig. 1), we decided to additionally analyze the injected host muscle using a human-specific antidystrophin antibody, because a low expression level of dysferlin in sjl mice (~15% of normal) was observed by Bittner et al [4] when using Western immunoblotting technique. After documenting that it does indeed show human-specific binding (Figs.…”

Section: Discussionmentioning

confidence: 99%

Human Umbilical Cord Blood Cells Differentiate into Muscle in sjl Muscular Dystrophy Mice

Kong

Ren²,

Kraus³

et al. 2004

STEM CELLS

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Limb girdle muscular dystrophy type 2B form (LGMD‐2B) and Miyoshi myopathy (MM) are both caused by mutations in the dysferlin (dysf) gene. In this study, we used dysferlin‐deficient sjl mice as a mouse model to study cell therapy for LGMD‐2B and MM. A single‐blind study evaluated the therapeutic potential of human umbilical cord blood (HUCB) as a source of myogenic progenitor stem cells. Three groups of donor cells were used: unfractionated mononuclear HUCB cells, HUCB subfractionated to enrich for cells that were negative for lineage surface markers (LIN−) and substantially enriched for the CD34 surface marker (CD34+), and irradiated control spleen cells. We administrated 1 × 106 donor cells to each animal intravenously and euthanized them at different time points (1–12 weeks) after transplantation. All animals were immunosuppressed (FK506 and leflunomide) from the day before the injection until the time of euthanasia. Immunohistochemical analyses documented that a small number of human cells from the whole HUCB and LIN−CD34+/−‐enriched HUCB subgroups engraft in the recipient muscle to express both dysferlin and human‐specific dystrophin at 12 weeks after transplantation. We conclude that myogenic progenitor cells are present in the HUCB, that they can disseminate into muscle after intravenous administration, and that they are capable of myogenic differentiation in host muscle.

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“…1,[35][36][37] The large size of the dysferlin gene makes the application of gene replacement strategies relatively problematic, unless shortened forms of the protein can be shown to be at least partially functional, as has been demonstrated for dystrophin (Krahn et al, personal communication).…”

Section: Dysferlinopathy (Lgmd2b)mentioning

confidence: 99%

Therapeutic Possibilities in the Autosomal Recessive Limb-Girdle Muscular Dystrophies

Straub

Bushby

2008

Neurotherapeutics

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Summary:Fourteen years ago, the first disease-causing mutation in a form of autosomal recessive limb-girdle muscular dystrophy was reported. Since then the number of genes has been extended to at least 14 and the phenotypic spectrum has been broadened. The generation of mouse models helped to improve our understanding of the pathogenesis of the disease and also served to study therapeutic possibilities. All autosomal recessive limb-girdle muscular dystrophies are rare diseases, which is one reason why there have been so very few controlled clinical trials. Other reasons are insufficient natural history data and the lack of standardized assessment criteria and validated outcome measures. Currently, therapeutic possibilities are mainly restricted to symptomatic treatment and the treatment of disease complications. On the other hand, new efforts in translational research and the development of molecular therapeutic approaches suggest that more promising clinical trials will be carried out in autosomal recessive limb-girdle muscular dystrophy in the next several years.

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Dysferlin deletion in SJL mice (SJL-Dysf) defines a natural model for limb girdle muscular dystrophy 2B

Cited by 190 publications

References 11 publications

Simultaneous Dystrophin and Dysferlin Deficiencies Associated with High-Level Expression of the Coxsackie and Adenovirus Receptor in Transgenic Mice

Simultaneous Dystrophin and Dysferlin Deficiencies Associated with High-Level Expression of the Coxsackie and Adenovirus Receptor in Transgenic Mice

Human Umbilical Cord Blood Cells Differentiate into Muscle in sjl Muscular Dystrophy Mice

Therapeutic Possibilities in the Autosomal Recessive Limb-Girdle Muscular Dystrophies

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