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The collagen VI-related myopathies: muscle meets its matrix

Nature Reviews Neurology volume 7, pages 379–390 (2011)Cite this article

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Abstract

The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes—COL6A1, COL6A2, and COL6A3—can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.

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Figure 1: Joint laxity and progressive joint contractures in patients with Ullrich CMD and Bethlem myopathy.
Figure 2: Immunohistochemical identification of collagen VI in the muscle.
Figure 3: Muscle MRI findings in patients with collagen VI-related myopathies.
Figure 4: Schematic diagram of the domains and organization of collagen VI.

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References

  1. Okada, M. et al. Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan. Neurology 69, 1035–1042 (2007).

    CAS  PubMed  Google Scholar 

  2. Norwood, F. L. et al. Prevalence of genetic muscle disease in northern England: in-depth analysis of a muscle clinic population. Brain 132, 3175–3186 (2009).

    PubMed Central  PubMed  Google Scholar 

  3. Peat, R. A. et al. Diagnosis and etiology of congenital muscular dystrophy. Neurology 71, 312–321 (2008).

    CAS  PubMed  Google Scholar 

  4. Ullrich, O. Congenital, atonic–sclerotic muscular dystrophy, an additional type of heredo-degenerative illness of the neuromuscular system [German]. Z. Ges. Neurol. Psychiat. 126, 171–201 (1930).

    Google Scholar 

  5. Ullrich, O. Congenital atonic–sclerotic muscular dystrophy [German]. Monatsschr. Kinderheilkd. 47, 502–510 (1930).

    Google Scholar 

  6. Furukawa, T. & Toyokura, Y. Congenital, hypotonic–sclerotic muscular dystrophy. J. Med. Genet. 14, 426–429 (1977).

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Nonaka, I. et al. A clinical and histological study of Ullrich's disease (congenital atonic-sclerotic muscular dystrophy). Neuropediatrics 12, 197–208 (1981).

    CAS  PubMed  Google Scholar 

  8. Voit, T. Congenital muscular dystrophies: 1997 update. Brain Dev. 20, 65–74 (1998).

    CAS  PubMed  Google Scholar 

  9. Bertini, E. & Pepe, G. Collagen type VI and related disorders: Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Eur. J. Paediatr. Neurol. 6, 193–198 (2002).

    PubMed  Google Scholar 

  10. Lampe, A. K. & Bushby, K. M. Collagen VI related muscle disorders. J. Med. Genet. 42, 673–685 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Nadeau, A. et al. Natural history of Ullrich congenital muscular dystrophy. Neurology 73, 25–31 (2009).

    CAS  PubMed  Google Scholar 

  12. Brinas, L. et al. Early onset collagen VI myopathies: genetic and clinical correlations. Ann. Neurol. 68, 511–520 (2010).

    CAS  PubMed  Google Scholar 

  13. Jöbsis, G. J., Boers, J. M., Barth, P. G. & de Visser, M. Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Brain 122, 649–655 (1999).

    PubMed  Google Scholar 

  14. Scacheri, P. C. et al. Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 58, 593–602 (2002).

    CAS  PubMed  Google Scholar 

  15. Bradley, W. G., Hudgson, P., Gardner-Medwin, D. & Walton, J. N. The syndrome of myosclerosis. J. Neurol. Neurosurg. Psychiatry 36, 651–660 (1973).

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Merlini, L. et al. Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71, 1245–1253 (2008).

    CAS  PubMed  Google Scholar 

  17. Voermans, N. C. et al. Clinical and molecular overlap between myopathies and inherited connective tissue diseases. Neuromuscul. Disord. 18, 843–856 (2008).

    CAS  PubMed  Google Scholar 

  18. Alexopoulos, L. G., Youn, I., Bonaldo, P. & Guilak, F. Developmental and osteoarthritic changes in Col6a1-knockout mice: biomechanics of type VI collagen in the cartilage pericellular matrix. Arthritis Rheum. 60, 771–779 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Kirschner, J. et al. Ullrich congenital muscular dystrophy: connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes. Am. J. Med. Genet. A 132A, 296–301 (2005).

    PubMed  Google Scholar 

  20. Voermans, N. C., Bönnemann, C. G., Lammens, M., van Engelen, B. G. & Hamel, B. C. Myopathy and polyneuropathy in an adolescent with the kyphoscoliotic type of Ehlers–Danlos syndrome. Am. J. Med. Genet. A 149A, 2311–2316 (2009).

    CAS  PubMed  Google Scholar 

  21. Voermans, N. C. et al. Ehlers–Danlos syndrome due to tenascin-X deficiency: muscle weakness and contractures support overlap with collagen VI myopathies. Am. J. Med. Genet A 143A, 2215–2219 (2007).

    CAS  PubMed  Google Scholar 

  22. Minamitani, T. et al. Modulation of collagen fibrillogenesis by tenascin-X and type VI collagen. Exp. Cell Res. 298, 305–315 (2004).

    CAS  PubMed  Google Scholar 

  23. Sipila, L. et al. Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines. J. Biol. Chem. 282, 33381–33388 (2007).

    PubMed  Google Scholar 

  24. Quijano-Roy, S. et al. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann. Neurol. 64, 177–186 (2008).

    PubMed  Google Scholar 

  25. Ferreiro, A. et al. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann. Neurol. 51, 750–759 (2002).

    CAS  PubMed  Google Scholar 

  26. Jungbluth, H. et al. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 59, 284–287 (2002).

    CAS  PubMed  Google Scholar 

  27. Voermans, N. C., Bönnemann, C. G., Hamel, B. C., Jungbluth, H. & van Engelen, B. G. Joint hypermobility as a distinctive feature in the differential diagnosis of myopathies. J. Neurol. 256, 13–27 (2009).

    CAS  PubMed  Google Scholar 

  28. Schessl, J. et al. Predominant fiber atrophy and fiber type disproportion in early ullrich disease. Muscle Nerve 38, 1184–1191 (2008).

    PubMed  Google Scholar 

  29. Ishikawa, H. et al. Ullrich disease: collagen VI deficiency: EM suggests a new basis for muscular weakness. Neurology 59, 920–923 (2002).

    CAS  PubMed  Google Scholar 

  30. Pan, T. C. et al. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype. Am. J. Hum. Genet. 73, 355–369 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Ishikawa, H. et al. Ullrich disease due to deficiency of collagen VI in the sarcolemma. Neurology 62, 620–623 (2004).

    CAS  PubMed  Google Scholar 

  32. Baker, N. L. et al. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum. Mol. Genet. 14, 279–293 (2005).

    CAS  PubMed  Google Scholar 

  33. Hicks, D. et al. A refined diagnostic algorithm for Bethlem myopathy. Neurology 70, 1192–1199 (2008).

    CAS  PubMed  Google Scholar 

  34. Jimenez-Mallebrera, C. et al. A comparative analysis of collagen VI production in muscle, skin and fibroblasts from 14 Ullrich congenital muscular dystrophy patients with dominant and recessive COL6A mutations. Neuromuscul. Disord. 16, 571–582 (2006).

    CAS  PubMed  Google Scholar 

  35. Deconinck, N. et al. Differentiating Emery–Dreifuss muscular dystrophy and collagen VI-related myopathies using a specific CT scanner pattern. Neuromuscul. Disord. 20, 517–523 (2010).

    CAS  PubMed  Google Scholar 

  36. Mercuri, E. et al. Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine. Ann. Neurol. 67, 201–208 (2010).

    PubMed  Google Scholar 

  37. Mercuri, E. et al. Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy. Neuromuscul. Disord. 15, 303–310 (2005).

    PubMed  Google Scholar 

  38. Bönnemann, C. G., Brockmann, K. & Hanefeld, F. Muscle ultrasound in Bethlem myopathy. Neuropediatrics 34, 335–336 (2003).

    PubMed  Google Scholar 

  39. Keene, D. R., Engvall, E. & Glanville, R. W. Ultrastructure of type VI collagen in human skin and cartilage suggests an anchoring function for this filamentous network. J. Cell Biol. 107, 1995–2006 (1988).

    CAS  PubMed  Google Scholar 

  40. Kuo, H. J., Maslen, C. L., Keene, D. R. & Glanville, R. W. Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen. J. Biol. Chem. 272, 26522–26529 (1997).

    CAS  PubMed  Google Scholar 

  41. Ritty, T. M., Roth, R. & Heuser, J. E. Tendon cell array isolation reveals a previously unknown fibrillin-2-containing macromolecular assembly. Structure 11, 1179–1188 (2003).

    CAS  PubMed  Google Scholar 

  42. Timpl, R. & Chu, M. L. in Extracellular Matrix Assembly and Structure ( eds Yurchenco, P. D. et al.) 207–242 (Academic Press, Orlando, 1994).

    Google Scholar 

  43. Fitzgerald, J., Rich, C., Zhou, F. H. & Hansen, U. Three novel collagen VI chains, α4(VI), α5(VI), and α6(VI). J. Biol. Chem. 283, 20170–20180 (2008).

    CAS  PubMed  Google Scholar 

  44. Gara, S. K. et al. Three novel collagen VI chains with high homology to the α3 chain. J. Biol. Chem. 283, 10658–10670 (2008).

    CAS  PubMed  Google Scholar 

  45. Sabatelli, P. et al. Expression of the collagen VI α5 and α6 chains in normal human skin and in skin of patients with collagen VI-related myopathies. J. Invest. Dermatol. 131, 99–107 (2011).

    CAS  PubMed  Google Scholar 

  46. Chu, M. L. et al. The structure of type VI collagen. Ann. N. Y Acad. Sci. 580, 55–63 (1990).

    CAS  PubMed  Google Scholar 

  47. Aigner, T., Hambach, L., Söder, S., Schlötzer-Schrehardt, U. & Pöschl, E. The C5 domain of Col6A3 is cleaved off from the Col6 fibrils immediately after secretion. Biochem. Biophys. Res. Commun. 290, 743–748 (2002).

    CAS  PubMed  Google Scholar 

  48. Engvall, E., Hessle, H. & Klier, G. Molecular assembly, secretion, and matrix deposition of type VI collagen. J. Cell Biol. 102, 703–710 (1986).

    CAS  PubMed  Google Scholar 

  49. Furthmayr, H., Wiedemann, H., Timpl, R., Odermatt, E. & Engel, J. Electron-microscopical approach to a structural model of intima collagen. Biochem. J. 211, 303–311 (1983).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Chu, M. L. et al. Amino acid sequence of the triple-helical domain of human collagen type VI. J. Biol. Chem. 263, 18601–18606 (1988).

    CAS  PubMed  Google Scholar 

  51. Colombatti, A. Mucignat, M. T. & Bonaldo, P. Secretion and matrix assembly of recombinant type VI collagen. J. Biol. Chem. 270, 13105–13111 (1995).

    CAS  PubMed  Google Scholar 

  52. Bonaldo, P., Russo, V., Bucciotti, F., Doliana, R. & Colombatti, A. Structural and functional features of the α3 chain indicate a bridging role for chicken collagen VI in connective tissues. Biochemistry 29, 1245–1254 (1990).

    CAS  PubMed  Google Scholar 

  53. Lamandé, S. R. et al. The role of the α3(VI) chain in collagen VI assembly. Expression of an α3(VI) chain lacking N-terminal modules N10-N7 restores collagen VI assembly, secretion, and matrix deposition in an α3(VI)-deficient cell line. J. Biol. Chem. 273, 7423–7430 (1998).

    PubMed  Google Scholar 

  54. Baldock, C., Sherratt, M. J., Shuttleworth, C. A. & Kielty, C. M. The supramolecular organization of collagen VI microfibrils. J. Mol. Biol. 330, 297–307 (2003).

    CAS  PubMed  Google Scholar 

  55. Wiberg, C. et al. Biglycan and decorin bind close to the N-terminal region of the collagen VI triple helix. J. Biol. Chem. 276, 18947–18952 (2001).

    CAS  PubMed  Google Scholar 

  56. Bowe, M. A., Mendis, D. B. & Fallon, J. R. The small leucine-rich repeat proteoglycan biglycan binds to α-dystroglycan and is upregulated in dystrophic muscle. J. Cell Biol. 148, 801–810 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Rafii, M. S. et al. Biglycan binds to α- and γ-sarcoglycan and regulates their expression during development. J. Cell Physiol. 209, 439–447 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Aumailley, M., Specks, U. & Timpl, R. Cell adhesion to type VI collagen. Biochem. Soc. Trans. 19, 843–847 (1991).

    CAS  PubMed  Google Scholar 

  59. Klein, G., Müller, C. A., Tillet, E., Chu, M. L. & Timpl, R. Collagen type VI in the human bone marrow microenvironment: a strong cytoadhesive component. Blood 86, 1740–1748 (1995).

    CAS  PubMed  Google Scholar 

  60. Kawahara, G. et al. Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease. Neurology 69, 1043–1049 (2007).

    CAS  PubMed  Google Scholar 

  61. Atkinson, J. C., Rühl, M., Becker, J., Ackermann, R. & Schuppan, D. Collagen VI regulates normal and transformed mesenchymal cell proliferation in vitro. Exp. Cell Res. 228, 283–291 (1996).

    CAS  PubMed  Google Scholar 

  62. Perris, R., Kuo, H. J., Glanville, R. W. & Bronner-Fraser, M. Collagen type VI in neural crest development: distribution in situ and interaction with cells in vitro. Dev. Dyn. 198, 135–49 (1993).

    CAS  PubMed  Google Scholar 

  63. Iyengar, P. et al. Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment. J. Clin. Invest. 115, 1163–1176 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Rühl, M. et al. Soluble collagen VI drives serum-starved fibroblasts through S phase and prevents apoptosis via down-regulation of Bax. J. Biol. Chem. 274, 34361–34368 (1999).

    PubMed  Google Scholar 

  65. Irwin, W. A. et al. Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat. Genet. 35, 367–371 (2003).

    CAS  PubMed  Google Scholar 

  66. Nakajima, I., Muroya, S., Tanabe, R. & Chikuni, K. Extracellular matrix development during differentiation into adipocytes with a unique increase in type V and VI collagen. Biol. Cell 94, 197–203 (2002).

    CAS  PubMed  Google Scholar 

  67. Zou, Y., Zhang, R. Z., Sabatelli, P., Chu, M. L. & Bönnemann, C. G. Muscle interstitial fibroblasts are the main source of collagen VI synthesis in skeletal muscle: implications for congenital muscular dystrophy types Ullrich and Bethlem. J. Neuropathol. Exp. Neurol. 67, 144–154 (2008).

    CAS  PubMed  Google Scholar 

  68. Braghetta, P. et al. An enhancer required for transcription of the Col6a1 gene in muscle connective tissue is induced by signals released from muscle cells. Exp. Cell Res. 314, 3508–3518 (2008).

    CAS  PubMed  Google Scholar 

  69. Bonaldo, P. et al. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum. Mol. Genet. 7, 2135–2140 (1998).

    CAS  PubMed  Google Scholar 

  70. Angelin, A. et al. Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proc. Natl Acad. Sci. USA 104, 991–996 (2007).

    CAS  PubMed  Google Scholar 

  71. Angelin, A., Bonaldo, P. & Bernardi, P. Altered threshold of the mitochondrial permeability transition pore in Ullrich congenital muscular dystrophy. Biochim. Biophys. Acta 1777, 893–896 (2008).

    CAS  PubMed  Google Scholar 

  72. Tiepolo, T. et al. The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice. Br. J. Pharmacol. 157, 1045–1052 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Palma, E. et al. Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Hum. Mol. Genet. 18, 2024–2031 (2009).

    CAS  PubMed  Google Scholar 

  74. Grumati, P. et al. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat. Med. 16, 1313–1320 (2010).

    CAS  PubMed  Google Scholar 

  75. Chiarugi, P. & Giannoni, E. Anoikis: a necessary death program for anchorage-dependent cells. Biochem. Pharmacol. 76, 1352–1364 (2008).

    CAS  PubMed  Google Scholar 

  76. Girgenrath, M., Dominov, J. A., Kostek, C. A. & Miller, J. B. Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy. J. Clin. Invest. 114, 1635–1639 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Miller, J. B. & Girgenrath, M. The role of apoptosis in neuromuscular diseases and prospects for anti-apoptosis therapy. Trends Mol. Med. 12, 279–286 (2006).

    CAS  PubMed  Google Scholar 

  78. Hayashi, Y. K. et al. Massive muscle cell degeneration in the early stage of merosin-deficient congenital muscular dystrophy. Neuromuscul. Disord. 11, 350–359 (2001).

    CAS  PubMed  Google Scholar 

  79. Kawahara, G. et al. Diminished binding of mutated collagen VI to the extracellular matrix surrounding myocytes. Muscle Nerve 38, 1192–1195 (2008).

    CAS  PubMed  Google Scholar 

  80. Lampe, A. K. et al. Exon skipping mutations in collagen VI are common and are predictive for severity and inheritance. Hum. Mutat. 29, 809–822 (2008).

    CAS  PubMed  Google Scholar 

  81. Foley, A. R. et al. Autosomal recessive inheritance of classic Bethlem myopathy. Neuromuscul. Disord. 19, 813–817 (2009).

    PubMed Central  PubMed  Google Scholar 

  82. Gualandi, F. et al. Autosomal recessive Bethlem myopathy. Neurology 73, 1883–1891 (2009).

    CAS  PubMed  Google Scholar 

  83. Camacho Vanegas, O. et al. Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc. Natl Acad. Sci. USA 98, 7516–7521 (2001).

    CAS  PubMed  Google Scholar 

  84. Lucarini, L. et al. A homozygous COL6A2 intron mutation causes in-frame triple-helical deletion and nonsense-mediated mRNA decay in a patient with Ullrich congenital muscular dystrophy. Hum. Genet. 117, 460–466 (2005).

    CAS  PubMed  Google Scholar 

  85. Lampe, A. K. et al. Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J. Med. Genet. 42, 108–120 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Demir, E. et al. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am. J. Hum. Genet. 70, 1446–1458 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Giusti, B. et al. Dominant and recessive COL6A1 mutations in Ullrich scleroatonic muscular dystrophy. Ann. Neurol. 58, 400–410 (2005).

    CAS  PubMed  Google Scholar 

  88. Pepe, G. et al. COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy. Ann. Neurol. 59, 190–195 (2006).

    CAS  PubMed  Google Scholar 

  89. Bovolenta, M. et al. Identification of a deep intronic mutation in the COL6A2 gene by a novel custom oligonucleotide CGH array designed to explore allelic and genetic heterogeneity in collagen VI-related myopathies. BMC Med. Genet. 11, 44 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Zhang, R. Z. et al. Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant. J. Biol. Chem. 285, 10005–10015 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Pepe, G. et al. A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the α1(VI) collagen chain in an italian family affected by Bethlem myopathy. Biochem. Biophys. Res. Commun. 258, 802–807 (1999).

    CAS  PubMed  Google Scholar 

  92. Vanegas, O. C. et al. Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy. Muscle Nerve 25, 513–519 (2002).

    CAS  PubMed  Google Scholar 

  93. Lucioli, S. et al. Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 64, 1931–1937 (2005).

    CAS  PubMed  Google Scholar 

  94. Jöbsis, G. J. et al. Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nat. Genet. 14, 113–115 (1996).

    PubMed  Google Scholar 

  95. Pepe, G. et al. A novel de novo mutation in the triple helix of the COL6A3 gene in a two-generation Italian family affected by Bethlem myopathy. A diagnostic approach in the mutations' screening of type VI collagen. Neuromuscul. Disord. 9, 264–271 (1999).

    CAS  PubMed  Google Scholar 

  96. Byers, P. H. Folding defects in fibrillar collagens. Philos. Trans. R. Soc. Lond. B Biol. Sci. 356, 151–158 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Lamandé, S. R. et al. Kinked collagen VI tetramers and reduced microfibril formation as a result of Bethlem myopathy and introduced triple helical glycine mutations. J. Biol. Chem. 277, 1949–1956 (2002).

    PubMed  Google Scholar 

  98. Pace, R. A. et al. Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity. Ann. Neurol. 64, 294–303 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Petrini, S. et al. Ullrich myopathy phenotype with secondary ColVI defect identified by confocal imaging and electron microscopy analysis. Neuromuscul. Disord. 17, 587–596 (2007).

    PubMed  Google Scholar 

  100. Allamand, V., Merlini, L. & Bushby, K. 166th ENMC International Workshop on Collagen type VI-related Myopathies, 22–24 May 2009, Naarden, The Netherlands. Neuromuscul. Disord. 20, 346–354 (2010).

    PubMed  Google Scholar 

  101. Wang, C. H. et al. Consensus statement on standard of care for congenital muscular dystrophies. J. Child. Neurol. 25, 1559–1581 (2010).

    PubMed Central  PubMed  Google Scholar 

  102. Merlini, L. et al. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc. Natl Acad. Sci. USA 105, 5225–5229 (2008).

    CAS  PubMed  Google Scholar 

  103. Hicks, D. et al. Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue. Brain 132, 147–155 (2009).

    CAS  PubMed  Google Scholar 

  104. Millay, D. P. et al. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy. Nat. Med. 14, 442–447 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Collins, J. & Bönnemann, C. G. Congenital muscular dystrophies: toward molecular therapeutic interventions. Curr. Neurol. Neurosci. Rep. 10, 83–91 (2010).

    CAS  PubMed  Google Scholar 

  106. Bethlem, J. & Wijngaarden, G. K. Benign myopathy, with autosomal dominant inheritance. A report on three pedigrees. Brain 99, 91–100 (1976).

    CAS  PubMed  Google Scholar 

  107. Mohire, M. D. et al. Early-onset benign autosomal dominant limb-girdle myopathy with contractures (Bethlem myopathy). Neurology 38, 573–580 (1988).

    CAS  PubMed  Google Scholar 

  108. Jöbsis, G. J. et al. Genetic localization of Bethlem myopathy. Neurology 46, 779–782 (1996).

    PubMed  Google Scholar 

  109. Pan, T. C. et al. Missense mutation in a von Willebrand factor type A domain of the α3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy. Hum. Mol. Genet. 7, 807–812 (1998).

    CAS  PubMed  Google Scholar 

  110. Bidanset, D. J. et al. Binding of the proteoglycan decorin to collagen type VI. J. Biol. Chem. 267, 5250–5256 (1992).

    CAS  PubMed  Google Scholar 

  111. Sasaki, T., Gohring, W., Pan, T. C., Chu, M. L. & Timpl, R. Binding of mouse and human fibulin-2 to extracellular matrix ligands. J. Mol. Biol. 254, 892–899 (1995).

    CAS  PubMed  Google Scholar 

  112. Tillet, E. et al. Recombinant expression and structural and binding properties of α1(VI) and α2(VI) chains of human collagen type VI. Eur. J. Biochem. 221, 177–185 (1994).

    CAS  Google Scholar 

  113. Finnis, M. L. & Gibson, M. A. Microfibril-associated glycoprotein-1 (MAGP-1) binds to the pepsin-resistant domain of the α3(VI) chain of type VI collagen. J. Biol. Chem. 272, 22817–22823 (1997).

    CAS  PubMed  Google Scholar 

  114. Specks, U. et al. Structure of recombinant N-terminal globule of type VI collagen alpha 3 chain and its binding to heparin and hyaluronan. EMBO J. 11, 4281–4290 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Brown, J. C., Mann, K., Wiedemann, H. & Timpl, R. Structure and binding properties of collagen type XIV isolated from human placenta. J. Cell Biol. 120, 557–567 (1993).

    CAS  PubMed  Google Scholar 

  116. Burg, M. A., Tillet, E., Timpl, R. & Stallcup, W. B. Binding of the NG2 proteoglycan to type VI collagen and other extracellular matrix molecules. J. Biol. Chem. 271, 26110–26116 (1996).

    CAS  PubMed  Google Scholar 

  117. Stallcup, W. B., Dahlin, K. & Healy, P. Interaction of the NG2 chondroitin sulfate proteoglycan with type VI collagen. J. Cell Biol. 111, 3177–3188 (1990).

    CAS  PubMed  Google Scholar 

  118. Nishiyama, A. & Stallcup, W. B. Expression of NG2 proteoglycan causes retention of type VI collagen on the cell surface. Mol. Biol. Cell 4, 1097–1108 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Wiberg, C., Heinegard, D., Wenglen, C., Timpl, R. & Morgelin, M. Biglycan organizes collagen VI into hexagonal-like networks resembling tissue structures. J. Biol. Chem. 277, 49120–49126 (2002).

    CAS  PubMed  Google Scholar 

  120. Wiberg, C. et al. Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and aggrecan. J. Biol. Chem. 278, 37698–37704 (2003).

    CAS  PubMed  Google Scholar 

  121. Pfaff, M. et al. Integrin and Arg-Gly-Asp dependence of cell adhesion to the native and unfolded triple helix of collagen type VI. Exp. Cell Res. 206, 167–176 (1993).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to thank members of his laboratory and participants of the 166th ENMC International Workshop on Collagen type VI-related Myopathies, for helpful discussions.

L. Barclay, freelance writer and reviewer, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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  1. Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, PO Box 5801, Bethesda, MD 20824, USA. carsten.bonnemann@nih.gov,

    Carsten G. Bönnemann

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Bönnemann, C. The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol 7, 379–390 (2011). https://doi.org/10.1038/nrneurol.2011.81

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