Aberrant mitochondria in a Bethlem myopathy patient with a homozygous amino acid substitution that destabilizes the collagen VI α2(VI) chain.

Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem myopathy is relatively mild, and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem myopathy is rare, and our understanding of the molecular pathology is limited.

Chain-specific antibodies for laminin-511.

Mouse monoclonal antibodies (mAbs) that bind to specific chains of laminin-511 (LM-511) have been developed. Antibody 2F12 binds to the LMα5 chain, 3G10 binds to the LMβ1 chain and 3C12 binds to the LMγ1 chain. These antibodies can be used to purify LM-511, to detect LM-511 in cell extracts or to detect the location of LM-511 in tissue by immunohistochemistry.

Collagen VI microfibril formation is abolished by an {alpha}2(VI) von Willebrand factor type A domain mutation in a patient with Ullrich congenital muscular dystrophy.

Collagen VI is an extracellular protein that most often contains the three genetically distinct polypeptide chains, α1(VI), α2(VI), and α3(VI), although three recently identified chains, α4(VI), α5(VI), and α6(VI), may replace α3(VI) in some situations. Each chain has a triple helix flanked by N- and C-terminal globular domains that share homology with the von Willebrand factor type A (VWA) domains. During biosynthesis, the three chains come together to form triple helical monomers, which then assemble into dimers and tetramers.

Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.

WARP is a recently identified extracellular matrix molecule with restricted expression in permanent cartilages and a distinct subset of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures. To understand the in vivo function of WARP, we generated a WARP-deficient mouse strain.

Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.

Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes.

Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway.

Evidence for a role of tumor-derived laminin-511 in the metastatic progression of breast cancer.

Most studies investigating laminins (LMs) in breast cancer have focused on LM-111 or LM-332. Little is known, however, about the expression and function of alpha5 chain-containing LM-511/521 during metastatic progression. Expression of LM-511/521 subunits was examined in genetically related breast tumor lines and corresponding primary tumors and metastases in a syngeneic mouse model using real-time quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry.

Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin, and laminin.

Human granzyme B (GrB) released from cytotoxic lymphocytes plays a key role in the induction of target cell apoptosis when internalized in the presence of perforin. Here we demonstrate that GrB also possesses a potent extracellular matrix remodeling activity. Both native and recombinant GrB caused detachment of immortalized and transformed cell lines, primary endothelial cells, and chondrocytes.

Strategies for the purification of laminin-10 for studies on colon cancer metastasis.

Signals from the epidermal growth factor (EGF) receptor family are thought to combine with integrin-dependent adhesion to laminins to contribute to disease progression and metastasis in cancer. To date, little is known about the mechanisms by which these signals interact. Recently, we have shown that the colon cancer cell line LIM1215 secretes and adheres to laminin-10 through multiple integrin receptors, and that EGF stimulates spreading and migration of these cells on the same substrate.