Abstract
Background
We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD).
Methods
Clinical data of probands were collected and muscle biopsies of patients were analyzed. Exons of COL6A1, COL6A2 and COL6A3 were analyzed by direct sequencing. Mutations in COL6A1, COL6A2 and COL6A3 were identified in 8 patients.
Results
Among these mutations, 5 were novel [three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain]. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions.
Conclusions
The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients.
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References
Ullrich O. Kongenitale, atonisch-sklerotische Muskeldystrophie, ein weiterer Typus der heredodegenerativen Erkrankungen des neuromuskulären Systems. Zeitschrift für die gesamte Neurologie und Psychiatrie 1930;126:171–201.
Mercuri E, Yuva Y, Brown SC, Brockington M, Kinali M, Jungbluth H, et al. Collagen VI involvement in Ullrich syndrome: a clinical, genetic, and immunohistochemical study. Neurology 2002;58:1354–1359.
Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet 2005;42:673–685.
Muntoni F, Bertini E, Bönnemann C, Brockington M, Brown S, Bushby K, et al. 98th ENMC International Workshop on Congenital Muscular Dystrophy (CMD), 7th Workshop of the International Consortium on CMD, 2nd Workshop of the MYO CLUSTER project GENRE. 26–28th October, 2001, Naarden, The Netherlands. Neuromuscul Disord 2002;12:889–896.
Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a century of exciting progress. Neuromuscul Disord 2004;14:635–649.
Briñas L, Richard P, Quijano-Roy S, Gartioux C, Ledeuil C, Lacène E, et al. Early onset collagen VI myopathies: Genetic and clinical correlations. Ann Neurol 2010;68:511–520.
Allamand V, Merlini L, Bushby K; Consortium for Collagen VI-Related Myopathies. 166th ENMC International Workshop on Collagen type VI-Related Myopathies, 22–24 May 2009, Naarden, the Netherlands. Neuromuscul Disord 2010;20:346–354.
Okada M, Kawahara G, Noguchi S, Sugie K, Murayama K, Nonaka I, et al. Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan. Neurology 2007;69:1035–1042.
Pace RA, Peat RA, Baker NL, Zamurs L, Mörgelin M, Irving M, et al. Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity. Ann Neurol 2008;64:294–303.
Schessl J, Zou Y, Bönnemann CG. Congenital Muscular Dystrophies and the Extracellular Matrix. Semin Pediatr Neurol 2006;13:80–89.
Pan TC, Zhang RZ, Sudano DG, Marie SK, Bönnemann CG, Chu ML. 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 2003;73:355–369.
Ishikawa H, Sugie K, Murayama K, Awaya A, Suzuki Y, Noguchi S, et al. Ullrich disease due to deficiency of collagen VI in the sarcolemma. Neurology 2004;62:620–623.
Ishikawa H, Sugie K, Murayama K, Ito M, Minami N, Nishino I, et al. Ullrich disease: collagen VI deficiency: EM suggests a new basis for muscular weakness. Neurology 2002;59:920–923.
Voit T, Tome FM. The congenital muscular dystrophies. In: Engel AG, Franzini-Armstrong C, eds. Myology-basic and clinical, 3rd ed. New York: McGraw-Hill, 2004:1203–1238.
Bönnemann CG. The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol 2011;7:379–390.
Lampe AK, Dunn DM, von Niederhausern AC, Hamil C, Aoyagi A, Laval SH, et al. Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. J Med Genet 2005;42:108–120.
Baker NL, Mörgelin M, Peat R, Goemans N, North KN, Bateman JF, et al. Dominant collagen VI mutations are a common cause of Ullrich congenital muscular dystrophy. Hum Mol Genet 2005;14:279–293.
Jimenez-Mallebrera C, Maioli MA, Kim J, Brown SC, Feng L, Lampe AK, 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 2006;16:571–582.
Myllyharju J, Kivirikko KI. Collagens and collagen related diseases. Ann Med 2001;33:7–21.
Nadeau A, Kinali M, Main M, Jimenez-Mallebrera C, Aloysius A, Clement E, et al. Natural history of Ullrich congenital muscular dystrophy. Neurology 2009;73:25–31.
Foley AR, Hu Y, Zou Y, Yang M, Medne L, Leach M, et al. Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy. Ann Neurol 2011;69:206–211.
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Zhang, YZ., Zhao, DH., Yang, HP. et al. Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy. World J Pediatr 10, 126–132 (2014). https://doi.org/10.1007/s12519-014-0481-1
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DOI: https://doi.org/10.1007/s12519-014-0481-1