Advertisement

Collagen Type VI Myopathies

  • Kate M. D. BushbyEmail author
  • James Collins
  • Debbie Hicks
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)

Abstract

Mutations in each of the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause two main types of muscle disorders: Ullrich congenital muscular dystrophy, a severe phenotype, and a mild to moderate phenotype Bethlem myopathy. Recently, two additional phenotypes, including a limb-girdle muscular dystrophy phenotype and an autosomal recessive myosclerosis reported in one family with mutations in COL6A2 have been reported. Collagen VI is an important component of the extracellular matrix which forms a microfibrillar network that is found in close association with the cell and surrounding basement membrane. Collagen VI is also found in the interstitial space of many tissues including muscle, tendon, skin, cartilage, and intervertebral discs. Thus, collagen VI mutations result in disorders with combined muscle and connective tissue involvement, including weakness, joint laxity and contractures, and abnormal skin findings.

In this review we highlight the four recognized clinical phenotypes of collagen VI related – myopathies; Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM), autosomal dominant limb-girdle muscular dystrophy phenotype and autosomal recessive myosclerosis. We discuss the diagnostic criteria of these disorders, the molecular pathogenesis, genetics, treatment, and related disorders.

Keywords

Mutations in collagen VI genes COL6A1 COL6A2 and COL6A3 Ullrich congenital muscular dystrophy Bethlem myopathy 

Abbreviations

AD

Autosomal Dominant

BM

Bethlem Myopathy

CCD

Central Core

CGH

Comparative Genomic Hybridization

CMD

Congenital Muscular Dystrophy

CsA

Cyclosporine A

DGC

Dystrophin-Glycoprotein Complex

ECM

Extracellular Matrix

EDMD

Emery-Dreifuss Muscular Dystrophy

EDS

Ehlers-Danlos Syndrome

EMG

Electromyography

GAPDH

Glyceraldehyde 3-phosphate Dehydrogenase

LGMD

Limb Girdle Muscular Dystrophy

MDC1A

Merosin-Deficient Congenital Muscular Dystrophy Type 1A

MDC1C

Congenital Muscular Dystrophy Type 1C

MDC1D

Congenital Muscular Dystrophy Type 1D

MRI

Magnetic Resonance Imaging

mRNA

Messenger Ribonucleic Acid

PTP

Permeability Transition Pore

siRNA

Short Interfering Ribonucleic Acid

SR

Sarcoplasmic Reticulum

TGF-β

Transforming Growth Factor beta

UCMD

Ullrich Congenital Muscular Dystrophy

vWFA

von Willebrand Factor Type A

References

  1. 1.
    Angelin A, Tiepolo T, Sabatelli P et al (2007) Mitochondrial dysfunction in the pathogenesis of Ullrich congenital muscular dystrophy and prospective therapy with cyclosporins. Proc Natl Acad Sci U S A 104:991–996PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Baker NL, Morgelin M, Peat R et al (2005) Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 14:279–293PubMedCrossRefGoogle Scholar
  3. 3.
    Bernasconi P, Di Blasi C, Mora M et al (1999) Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies. Neuromuscul Disord 9:28–33PubMedCrossRefGoogle Scholar
  4. 4.
    Bethlem J, Wijngaarden GK (1976) Benign myopathy, with autosomal dominant inheritance. A report on three pedigrees. Brain 99:91–100PubMedCrossRefGoogle Scholar
  5. 5.
    Bonaldo P, Braghetta P, Zanetti M et al (1998) Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 7:2135–2140PubMedCrossRefGoogle Scholar
  6. 6.
    Bonnemann CG, Brockmann K, Hanefeld F (2003) Muscle ultrasound in Bethlem myopathy. Neuropediatrics 34:335–336PubMedCrossRefGoogle Scholar
  7. 7.
    Bovolenta M, Neri M, Martoni E et al (2010) 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 11:44PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Bradley WG, Hudgson P, Gardner-Medwin D et al (1973) The syndrome of myosclerosis. J Neurol Neurosurg Psychiatry 36:651–660PubMedCrossRefGoogle Scholar
  9. 9.
    Braghetta P, Ferrari A, Fabbro C et al (2008) An enhancer required for transcription of the Col6a1 gene in muscle connective tissue is induced by signals released from muscle cells. Exp Cell Res 314:3508–3518PubMedCrossRefGoogle Scholar
  10. 10.
    Briñas L, Richard P, Quijano-Roy S et al (2010) Early onset collagen VI myopathies: genetic and clinical correlations. Ann Neurol 68:511–520PubMedCrossRefGoogle Scholar
  11. 11.
    Camacho Vanegas O, Bertini E, Zhang RZ et al (2001) Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. Proc Natl Acad Sci U S A 98:7516–7521PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Carlile GW, Chalmers-Redman RM, Tatton NA et al (2000) Reduced apoptosis after nerve growth factor and serum withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehydrogenase to a dimer. Mol Pharmacol 57:2–12PubMedGoogle Scholar
  13. 13.
    Chu ML, Pan TC, Conway D et al (1990) The structure of type VI collagen. Ann N Y Acad Sci 580:55–63PubMedCrossRefGoogle Scholar
  14. 14.
    Cohn RD, Van Erp C, Habashi JP et al (2007) Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 13:204–210PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Demir E, Sabatelli P, Allamand V et al (2002) Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet 70:1446–1458PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Dziadek M, Darling P, Bakker M et al (1996) Deposition of collagen VI in the extracellular matrix during mouse embryogenesis correlates with expression of the [alpha]3(VI) subunit gene. Exp Cell Res 226:302–315PubMedCrossRefGoogle Scholar
  17. 17.
    Elbaz M, Yanay N, Aga-Mizrachi S et al (2012) Losartan, a therapeutic candidate in congenital muscular dystrophy: studies in the dy(2J)/dy(2J) mouse. Ann Neurol 71:699–708PubMedCrossRefGoogle Scholar
  18. 18.
    Engvall E, Hessle H, Klier G (1986) Molecular assembly, secretion, and matrix deposition of type VI collagen. J Cell Biol 102:703–710PubMedCrossRefGoogle Scholar
  19. 19.
    Erb M, Meinen S, Barzaghi P et al (2009) Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency. J Pharmacol Exp Ther 331:787–795PubMedCrossRefGoogle Scholar
  20. 20.
    Foley AR, Hu Y, Zou Y et al (2009) Autosomal recessive inheritance of classic Bethlem myopathy. Neuromuscul Disord 19:813–817PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Foley AR, Hu Y, Zou Y et al (2011) Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy. Ann Neurol 69:206–211PubMedCrossRefGoogle Scholar
  22. 22.
    Furthmayr H, Wiedemann H, Timpl R et al (1983) Electron-microscopical approach to a structural model of intima collagen. Biochem J 211:303–311PubMedGoogle Scholar
  23. 23.
    Grumati P, Coletto L, Sabatelli P et al (2010) Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16:1313–1320PubMedCrossRefGoogle Scholar
  24. 24.
    Gualandi FM, Urciuolo AB, Martoni EP et al (2009) Autosomal recessive Bethlem myopathy. Neurology 73:1883–1891PubMedCrossRefGoogle Scholar
  25. 25.
    Hansson MJ, Mattiasson G, Mansson R et al (2004) The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr 36:407–413PubMedCrossRefGoogle Scholar
  26. 26.
    Haq RU, Speer MC, Chu ML et al (1999) Respiratory muscle involvement in Bethlem myopathy. Neurology 52:174–176PubMedCrossRefGoogle Scholar
  27. 27.
    Heiskanen M, Saitta B, Palotie A et al (1995) Head to tail organization of the human COL6A1 and COL6A2 genes by fiber-FISH. Genomics 29:801–803PubMedCrossRefGoogle Scholar
  28. 28.
    Hicks D, Lampe AK, Barresi R et al (2008) A refined diagnostic algorithm for Bethlem myopathy. Neurology 70:1192–1199PubMedCrossRefGoogle Scholar
  29. 29.
    Hicks D, Lampe AK, Laval SH et al (2009) Cyclosporine a treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue. Brain 132:147–155PubMedCrossRefGoogle Scholar
  30. 30.
    Higuchi I, Horikiri T, Niiyama T et al (2003) Pathological characteristics of skeletal muscle in Ullrich’s disease with collagen VI deficiency. Neuromuscul Disord 13:310–316PubMedCrossRefGoogle Scholar
  31. 31.
    Irwin WA, Bergamin N, Sabatelli P et al (2003) Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat Genet 35:367–371PubMedCrossRefGoogle Scholar
  32. 32.
    Ishikawa H, Sugie K, Murayama K et al (2004) Ullrich disease due to deficiency of collagen VI in the sarcolemma. Neurology 62:620–623PubMedCrossRefGoogle Scholar
  33. 33.
    Ishikawa H, Sugie K, Murayama K et al (2002) Ullrich disease: collagen VI deficiency: EM suggests a new basis for muscular weakness. Neurology 59:920–923PubMedCrossRefGoogle Scholar
  34. 34.
    Jimenez-Mallebrera C, Maioli MA, Kim J et al (2006) 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 16:571–582PubMedCrossRefGoogle Scholar
  35. 35.
    Jobsis GJ, Keizers H, Vreijling JP et al (1996) Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy with contractures. Nat Genet 14:113–115PubMedCrossRefGoogle Scholar
  36. 36.
    Jungbluth H, Davis MR, Muller C et al (2004) Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 14:785–790PubMedCrossRefGoogle Scholar
  37. 37.
    Kawahara G, Ogawa M, May MO et al (2008) Diminished binding of mutated collagen VI to the extracellular matrix surrounding myocytes. Muscle Nerve 38:1192–1195PubMedCrossRefGoogle Scholar
  38. 38.
    Kawahara GP, Okada MM, Morone NP et al (2007) Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease. Neurology 69:1043–1049PubMedCrossRefGoogle Scholar
  39. 39.
    Kragten E, Lalande I, Zimmermann K et al (1998) Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(−)-deprenyl. J Biol Chem 273:5821–5828PubMedCrossRefGoogle Scholar
  40. 40.
    Lamande SR, Bateman JF (1999) Procollagen folding and assembly: the role of endoplasmic reticulum enzymes and molecular chaperones. Semin Cell Dev Biol 10:455–464PubMedCrossRefGoogle Scholar
  41. 41.
    Lamande SR, Morgelin M, Selan C et al (2002) Kinked collagen VI tetramers and reduced microfibril formation as a result of Bethlem myopathy and introduced triple helical glycine mutations. J Biol Chem 277:1949–1956PubMedCrossRefGoogle Scholar
  42. 42.
    Lamande SR, Sigalas E, Pan TC et al (1998) The role of the alpha3(VI) chain in collagen VI assembly. Expression of an alpha3(VI) chain lacking N-terminal modules N10-N7 restores collagen VI assembly, secretion, and matrix deposition in an alpha3(VI)-deficient cell line. J Biol Chem 273:7423–7430PubMedCrossRefGoogle Scholar
  43. 43.
    Lampe AK, Bushby KM (2005) Collagen VI related muscle disorders. J Med Genet 42:673–685PubMedCrossRefGoogle Scholar
  44. 44.
    Lucioli S, Giusti B, Mercuri E et al (2005) Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. Neurology 64:1931–1937PubMedCrossRefGoogle Scholar
  45. 45.
    Mercuri E, Cini C, Pichiecchio A et al (2003) Muscle magnetic resonance imaging in patients with congenital muscular dystrophy and Ullrich phenotype. Neuromuscul Disord 13:554–558PubMedCrossRefGoogle Scholar
  46. 46.
    Mercuri E, Counsell S, Allsop J et al (2002) Selective muscle involvement on magnetic resonance imaging in autosomal dominant Emery-Dreifuss muscular dystrophy. Neuropediatrics 33:10–14PubMedCrossRefGoogle Scholar
  47. 47.
    Mercuri E, Lampe A, Allsop J et al (2005) Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy. Neuromuscul Disord 15:303–310PubMedCrossRefGoogle Scholar
  48. 48.
    Merlini L, Angelin A, Tiepolo T et al (2008) Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies. Proc Natl Acad Sci U S A 105:5225–5229PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Merlini L, Martoni E, Grumati P et al (2008) Autosomal recessive myosclerosis myopathy is a collagen VI disorder. Neurology 71:1245–1253PubMedCrossRefGoogle Scholar
  50. 50.
    Merlini L, Morandi L, Granata C et al (1994) Bethlem myopathy: early-onset benign autosomal dominant myopathy with contractures. Description of two new families. Neuromuscul Disord 4:503–511PubMedCrossRefGoogle Scholar
  51. 51.
    Muntoni F, Bertini E, Bonnemann C et al (2002) 98th ENMC international workshop on Congenital Muscular Dystrophy (CMD). In: 7th workshop of the international consortium on CMD, 2nd workshop of the MYO CLUSTER project GENRE, Naarden, 26–28 Oct 2001. Neuromuscul Disord 12:889–896Google Scholar
  52. 52.
    Nadeau A, Kinali M, Main M et al (2009) Natural history of Ullrich congenital muscular dystrophy. Neurology 73:25–31PubMedCrossRefGoogle Scholar
  53. 53.
  54. 54.
    Palma E, Tiepolo T, Angelin A et al (2009) Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Hum Mol Genet 18:2024–2031PubMedCrossRefGoogle Scholar
  55. 55.
    Pan TC, Zhang RZ, Sudano DG et al (2003) 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 73:355–369PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Peat RA, Baker NL, Jones KJ et al (2007) Variable penetrance of COL6A1 null mutations: Implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families. Neuromuscul Disord 17:547–557PubMedCrossRefGoogle Scholar
  57. 57.
    Pepe G, Bertini E, Bonaldo P et al (2002) Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 23–24 November 2001, Naarden, The Netherlands. Neuromuscul Disord 12:984–993PubMedCrossRefGoogle Scholar
  58. 58.
    Pepe G, Bertini E, Giusti B et al (1999) 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 9:264–271PubMedCrossRefGoogle Scholar
  59. 59.
    Pepe G, Giusti B, Bertini E et al (1999) A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha1(VI) collagen chain in an Italian family affected by Bethlem myopathy. Biochem Biophys Res Commun 258:802–807PubMedCrossRefGoogle Scholar
  60. 60.
    Pepe G, Lucarini L, Zhang R-Z et al (2006) COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy. Ann Neurol 59:190–195PubMedCrossRefGoogle Scholar
  61. 61.
    Quijano-Roy S, Mbieleu B, Bonnemann CG et al (2008) De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann Neurol 64:177–186PubMedCrossRefGoogle Scholar
  62. 62.
    Sabatelli P, Bonaldo P, Lattanzi G et al (2001) Collagen VI deficiency affects the organization of fibronectin in the extracellular matrix of cultured fibroblasts. Matrix Biol 20:475–486PubMedCrossRefGoogle Scholar
  63. 63.
    Sanes JR (2003) The basement membrane/basal lamina of skeletal muscle.[see comment]. J Biol Chem 278:12601–12604PubMedCrossRefGoogle Scholar
  64. 64.
    Scacheri PC, Gillanders EM, Subramony SH et al (2002) Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. Neurology 58:593–602PubMedCrossRefGoogle Scholar
  65. 65.
    Schara U, Kress W, Bonnemann CG et al (2008) The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy. Eur J Paediatr Neurol 12:224–230PubMedCrossRefGoogle Scholar
  66. 66.
    Somer H, Laulumaa V, Paljarvi L et al (1991) Benign muscular dystrophy with autosomal dominant inheritance. Neuromuscul Disord 1:267–273PubMedCrossRefGoogle Scholar
  67. 67.
    Telfer WR, Busta AS, Bonnemann CG et al (2010) Zebrafish models of collagen VI-related myopathies. Hum Mol Genet 19:2433–2444PubMedCrossRefGoogle Scholar
  68. 68.
    Tiepolo T, Angelin A, Palma E et al (2009) The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1(−/−) myopathic mice. Br J Pharmacol 157:1045–1052PubMedCrossRefGoogle Scholar
  69. 69.
    Usuki F, Yamashita A, Higuchi I et al (2004) Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich’s disease. Ann Neurol 55:740–744PubMedCrossRefGoogle Scholar
  70. 70.
    Usuki F, Yamashita A, Kashima I et al (2006) Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. Mol Ther J Am Soc Gene Ther 14:351–360CrossRefGoogle Scholar
  71. 71.
    Vanegas OC, Zhang RZ, Sabatelli P et al (2002) Novel COL6A1 splicing mutation in a family affected by mild Bethlem myopathy. Muscle Nerve 25:513–519PubMedCrossRefGoogle Scholar
  72. 72.
    Walchli C, Koller E, Trueb J et al (1992) Structural comparison of the chicken genes for alpha1(VI) and alpha2(VI) collagen. Eur J Biochem 205:583–589PubMedCrossRefGoogle Scholar
  73. 73.
    Wallgren-Pettersson C, Pelin K, Nowak KJ et al (2004) Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord 14:461–470PubMedCrossRefGoogle Scholar
  74. 74.
    Wang CH, Bonnemann CG, Rutkowski A et al (2010) Consensus statement on standard of care for congenital muscular dystrophies. J Child Neurol 25:1559–1581PubMedCrossRefGoogle Scholar
  75. 75.
    Weil D, Mattei MG, Passage E et al (1988) Cloning and chromosomal localization of human genes encoding the three chains of type VI collagen. Am J Hum Genet 42:435–445PubMedCentralPubMedGoogle Scholar
  76. 76.
    Zhang RZ, Sabatelli P, Pan TC et al (2002) Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy. J Biol Chem 277:43557–43564PubMedCrossRefGoogle Scholar
  77. 77.
    Zou Y, Zhang RZ, Sabatelli P et al (2008) 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 67:144–154PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Kate M. D. Bushby
    • 1
    Email author
  • James Collins
    • 2
  • Debbie Hicks
    • 1
  1. 1.Institute of Genetic MedicineNewcastle University, International Centre for LifeNewcastle upon TyneUK
  2. 2.Department of Pediatric NeurologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations