Localization and Quantitation of the Chromosome 6-Encoded Dystrophin-Related Protein in Normal and Pathological Human Muscle

Mice rendered null for ␣-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, ␣-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAM-AGE associates directly with ␣-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of ␣-dystrobrevin but not ␤-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279 -288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

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“…␣-Dystrobrevin is also present in this structure (Fig. 8A), as is the dystrophin homologue utrophin (43,44).…”

Section: ␣-Dystrobrevin Interaction With Damage/mage-e1mentioning

confidence: 86%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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“…One is that in human states of primary dystrophin deficiency (Duchenne or Becker muscular dystrophies), there is a decrease of the sarcolemmal ␤-dystroglycan 56 but an increase of extrasynaptic utrophin. 57 By contrast, in the CAR ϩ/ϩ transgenics, in which there is substantial dystrophin deficiency, ␤-dystroglycan is up-regulated, and extrasynaptic utrophin is not seen. Secondly, a substantial de novo up-regulation of caveolin-3 has not been described in human muscle disease.…”

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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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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“…During myo-and synaptogenesis, expression of utrophin appears modulated such that increased levels of expression have been reported in both embryonic and neo-natal muscles [5,18,19,22,27,30,31]. In mdx mouse muscles, levels of utrophin decrease progressively reaching minimal levels three to four weeks after birth [31].…”

Section: Discussionmentioning

confidence: 99%

“…Fax: (1) (613) 562-5434. DMD patients [19,[26][27][28][29] as well as in embryonic and neo-natal muscles ( [5,18,19,22,30,31], see also [27]). Recently, it was also reported that some muscles of mdx mice may contain significantly more utrophin in comparison to normal mouse muscles [321.…”

Section: Introductionmentioning

confidence: 99%

Expression of utrophin and its mRNA in denervated mdx mouse muscle

et al. 1995

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Utrophin is a large cytoskeletal protein which shows high homology to dystrophin. In contrast to the sarcolemmal distribution of dystrophin, utrophin accumulates at the postsynaptic membrane of the neuromuscular junction. Because of its localization within this compartment of muscle fibers, expression of utrophin may be significantly influenced by the presence of the motor nerve. We tested this hypothesis by denervating muscles of mdx mouse and monitoring levels of utrophin and its mRNA by immunofluorescence, immunobiotting and RT-PCR. A significant increase in the number of utrophin positive fibers was observed by immunofluorescence 3 to 21 days after sectioning of the sciatic nerve. Quantitative analyses of utrophin and its transcripts in hindlimb muscles denervated for two weeks showed only a moderate increase in the levels of both utrophin (~ 2-fold) and its transcript (-60 to 90%). The present data suggest that although utrophin is a component of the postsynaptic membrane, its neural regulation is distinct from that of the acetylcholine receptor.

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Localization and Quantitation of the Chromosome 6-Encoded Dystrophin-Related Protein in Normal and Pathological Human Muscle

Cited by 136 publications

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DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

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

Expression of utrophin and its mRNA in denervated mdx mouse muscle

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