Genetic localization of Bethlem myopathy

Jöbsis, G. Joost; Bolhuis, P. A.; Boers, J.M.; Baas, Frank; Wolterman, Ruud A.; Hensels, G. W.; Visser, Marjolein

doi:10.1212/wnl.46.3.779

Cited by 41 publications

(18 citation statements)

References 7 publications

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“…The initial characterization of these collagen VIα1 -/-animals revealed no striking phenotypic changes except mild histological signs of myopathy in skeletal muscle of both homo-and heterozygous mutant animals (19). This myopathy resembled pathologically Bethlem myopathy, a human inherited syndrome correlated with collagen VI genes (21)(22)(23). Subsequent characterization has revealed mitochondrial dysfunction and increased levels of apoptosis in myocytes of these mice (24).…”

Section: Resultsmentioning

confidence: 93%

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Iyengar¹,

Espina²,

Williams³

et al. 2005

J. Clin. Invest.

354

247

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The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen -/-mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growthstimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the fulllength molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.

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Section: Resultsmentioning

confidence: 93%

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Iyengar¹,

Espina²,

Williams³

et al. 2005

J. Clin. Invest.

354

247

View full text Add to dashboard Cite

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“…This, together with the known distribution and properties of type VI collagen, made it a good candidate molecule. Mutations in the triple helical region of the ␣1(VI) chain in one family and the ␣2(VI) chain in two families have recently been identified (18), and the ␣3(VI) chain gene still remains a candidate for other families (46). In general, muscular dystrophies are caused by a disturbance of the attachment of muscle cells to their basement membrane (47).…”

Section: Discussionmentioning

confidence: 99%

“…The results described here indicate a newly discovered direct interaction of intact native type VI collagen with type IV collagen, a major component of basement membranes. This interaction is significant because it is the first type VI collagen protein-protein interaction with a basement membrane component that has been characterized, and it provides an plausible explanation for the Bethlem myopathy phenotype, a genetic disease caused by mutations in type VI collagen (18).…”

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confidence: 99%

Type VI Collagen Anchors Endothelial Basement Membranes by Interacting with Type IV Collagen

Kuo

Maslen

Keene

et al. 1997

Journal of Biological Chemistry

297

215

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Type VI collagen filaments are found associated with interstitial collagen fibers, around cells, and in contact with endothelial basement membranes. To identify type VI collagen binding proteins, the amino-terminal domains of the ␣1(VI) and ␣2(VI) chains and a part of the carboxyl-terminal domain of the ␣3(VI) chain were used as bait in a yeast two-hybrid system to screen a human placenta library. Eight persistently positive clones were identified, two coding the known matrix proteins fibronectin and basement membrane type IV collagen and the rest coding new proteins. The amino-terminal domain of ␣1(VI) was shown to interact with the carboxylterminal globular domain of type IV collagen. The specificity of this interaction was further studied using the yeast two-hybrid system in a one-on-one format and confirmed by using isolated protein domains in immunoprecipitation, affinity blots, and enzyme-linked immunosorbent assay-based binding studies. Co-distribution of type VI and type IV collagens in human muscle was demonstrated using double labeling immunofluorescent microscopy and immunoelectron microscopy. The strong interaction of type VI collagen filaments with basement membrane collagen provided a possible molecular pathogenesis for the heritable disorder Bethlem myopathy.Type VI collagen filaments are ubiquitous. They are present in all connective tissues that contain type I and type III collagen fibers and in cartilage, a tissue that contains predominantly type II collagen. The major functions that have been suggested for type VI collagen filamentous networks are as a substrate for cell attachment and as an anchoring meshwork that connects collagen fibers, nerves, and blood vessels to the surrounding matrix (1, 2). This implies that not only is there an interaction, either direct or indirect, with the type I/III collagen fibers but also that there is an interaction with components of endothelial basement membranes.Matrix components that have been shown to interact with type VI collagen in vitro include proteoglycans, collagens, hyaluronan, heparin, and integrins.Proteoglycans appear to be particularly important, since cell surface-, basement membrane-, and collagen fibril-associated proteoglycans have all been reported to bind to various forms of type VI collagen. Decorin is a small dermatan sulfate proteoglycan that binds to fibrillar collagens (3). It was shown that the leucine-rich module of the core protein bound to type VI and that the binding could be inhibited by the core proteins of fibromodulin and biglycan (4). The cell surface-associated membrane chondroitin sulfate proteoglycan NG2 was originally detected in cells from the rodent central nervous system but subsequently was also detected in blood vessels and cartilaginous structures of the head, neck, and spine. It interacts via its core protein with type VI collagen and is thought to provide machinery for transmembrane signaling (5). Since ␣1␤1 and ␣2␤1 integrins also bind type VI collagen (6, 7), the cell signaling potential of this molecule woul...

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“…In addition, SSR markers encompassing the loci of autosomal recessive HIBM (AR-HIBM), 15 autosomal dominant HIBM (AD-HIBM), 16 Bethlem myopathy, [17][18] and facioscapulohumeral dystrophy (FSHD) 19 were genotyped.…”

Section: Methodsmentioning

confidence: 99%