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Reduced cell anchorage may cause sarcolemma-specific collagen VI deficiency in Ullrich disease

From the Department of Neuromuscular Research (G.K., M.O., C.A.I., I. Nonaka, S.N., Y.K.H., I. Nishino), the Department of Ultrastructural Research (N.M.), National Institute of Neuroscience National Center of Neurology and Psychiatry (NCNP), Kodaira; and Second Department of Pediatrics (M.O.), Toho University School of Medicine, Tokyo, Japan.

Address correspondence and reprint requests to Dr. Ichizo Nishino, Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo, 187-8502 Japan nishino{at}ncnp.go.jp

Background: COL6 gene mutations are associated with Ullrich congenital muscular dystrophy (UCMD), which is clinically characterized by muscle weakness from early infancy, hyperlaxity of distal joints, and multiple proximal joint contractures. We previously reported that the majority of patients with UCMD have sarcolemma-specific collagen VI deficiency (SSCD). More recently, we found heterozygous COL6A1 glycine substitutions in patients with UCMD with SSCD.

Objective: To elucidate how COL6A1 glycine mutation leads to SSCD.

Methods: We evaluated the synthesis, formation, and binding of collagen VI to the extracellular matrix in fibroblasts with p.G284R mutation in COL6A1.

Results: Collagen VI was normally secreted into the cultured medium in fibroblasts harboring p.G284R mutation. When the medium with normal collagen VI was added to collagen VI-deficient fibroblast culture, collagen VI bound surrounding the cells, while collagen VI with p.G284R mutation did not. Cell adhesion of fibroblasts with p.G284R mutation was markedly reduced similarly to that of collagen VI–deficient cells. Interestingly, this reduction in adhesion of the cells with p.G284R mutation was recovered by the addition of the medium with normal collagen VI, which would suggest a therapeutic strategy for a replacement therapy.

Conclusion: Heterozygous glycine substitution in COL6A1 may cause decreased binding of collagen VI microfibrils to the extracellular matrix resulting in sarcolemma-specific collagen VI deficiency.

Supplemental data at www.neurology.org

See also page 1035

Supported in part by the "Research on Health Sciences focusing on Drug Innovation" from the Japanese Health Sciences Foundation; by the "Research on Psychiatric and Neurological Diseases and Mental Health" of "Health and Labor Sciences Research Grants" and the "Research Grant (17A-10, 16B-2) for Nervous and Mental Disorders," from the Ministry of Health, Labor and Welfare; by the "Grant-in-Aid for Scientific Research" from the Japan Society for the Promotion of Science; by the Nakatomi Foundation; and by the "Program for Promotion of Fundamental Studies in Health Sciences" of the National Institute of Biomedical Innovation (NIBIO).

Disclosure: The authors report no conflicts of interest.

Received December 28, 2006. Accepted in final form April 9, 2007.

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Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan

M. Okada, G. Kawahara, S. Noguchi, K. Sugie, K. Murayama, I. Nonaka, Y. K. Hayashi, and I. Nishino
Neurology 2007 69: 1035-1042. [Abstract] [Full Text]  

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				M. Okada, G. Kawahara, S. Noguchi, K. Sugie, K. Murayama, I. Nonaka, Y. K. Hayashi, and I. Nishino Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan Neurology, September 4, 2007; 69(10): 1035 - 1042. [Abstract] [Full Text] [PDF]