5 research outputs found
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. Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced. Interpretation: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity
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. WARP-null mice were healthy, viable, and fertile
with no overt abnormalities. Motor function and behavioral testing
demonstrated that WARP-null mice exhibited a significantly delayed response to
acute painful stimulus and impaired fine motor coordination, although general
motor function was not affected, suggesting compromised peripheral nerve
function. Immunostaining of WARP-interacting ligands demonstrated that the
collagen VI microfibrillar matrix was severely reduced and mislocalized in
peripheral nerves of WARP-null mice. Further ultrastructural analysis revealed
reduced fibrillar collagen deposition within the peripheral nerve
extracellular matrix and abnormal partial fusing of adjacent Schwann cell
basement membranes, suggesting an important function for WARP in stabilizing
the association of the collagenous interstitial matrix with the Schwann cell
basement membrane. In contrast, other WARP-deficient tissues such as articular
cartilage, intervertebral discs, and skeletal muscle showed no detectable
abnormalities, and basement membranes formed normally. Our data demonstrate
that although WARP is not essential for basement membrane formation or
musculoskeletal development, it has critical roles in the structure and
function of peripheral nerves