Carsten Bönnemann, M.D.

Division of Neurology, The Children's Hospital of Philadelphia

Contact Information

Abramson Research Center Rm 516A
34th Str & Civic Ctr Blvd
Philadelphia, PA 19104
Phone: (215) 590-7490
Fax: (215) 590-3709
E-mail: BONNEMANN@email.chop.edu

Research Summary

The overall aim of the laboratory is to better understand the interactions between muscle and its extracellular matrix and the role this interface plays in diseases of muscle. We are approaching this question coming from the muscle membrane as well as from the extracellular matrix taking our leads from different types of limb-girdle muscular dystrophy (LGMD) and congenital muscular dystrophy (CMD).

The dystrophin-associated proteins appear to be part of such a link to the extracellular matrix. The sarcoglycan (SG) complex, which comprises a portion of these proteins, is composed of α-, β-, γ-, and δ-SG. Mutations in all four of these molecules cause muscular dystrophies, but the normal functions of the SG complex are not understood. SG can be viewed as a receptor the ligands of which are mostly still elusive. β- and δ-SG are most tightly associated, they form a core-complex within SG. To elucidate the basic functions of the SG complex we will try to identify and characterize ligands for this core complex, using a number of different tool. Ligands identified in this way will be studied to determine their normal function and involvement in muscular dystrophy, including as a candidate for novel forms of muscular dystrophy.

Within the extracellular matrix we are concentrating on CMD type Ullrich, a genetically heterogeneous phenotype that includes marked joint hyperlaxity in addition to congenital weakness. While mutations in collagen type VI (COL6) account for some patients with this phenotype, others have normal COL6 studies. We are studying COL6 deficiency dependent changes in patients with COL6 mutations, and in addition compare COL6 deficient patients with Ullrich type CMD patients in whom COL6 is normal. This comparative analysis on both protein and gene expression levels (using array technology) is aimed at identifying novel genetic causes for Ullrich type CMD that may help to elucidate the extracellular molecular chain of which COL6 is a part.

Representative Publications

1. C.G. Bönnemann, J. Wong, K. Jones, H.G.W. Lidov, C.A. Feener, F. Shapiro, B.T. Darras, L.M. Kunkel, K. North: Primary g-sarcoglycanopathy (LGMD 2C): Broadening of the mutational spectrum and diagnostic value of the immunohistochemical profile. Neuromuscular Disord, 12: 273-280 (2002).
2. C.G. Bönnemann, G.F. Cox, F. Shapiro, J.J. Wu, C.A. Feener, T.G. Thompson, D.C. Anthony, D.R. Eyre, B.T. Darras, L.M. Kunkel: A mutation in the a3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc Natl Acad Sci USA 97: 1212-1217 (2000).
3. Y. Chan, C.G. Bönnemann, H.G.W. Lidov, L.M. Kunkel: Molecular organization of sarcoglycan complex in mouse myotubes in culture. J Cell Biol 143: 2033-2044 (1998).
4. C.G. Bönnemann, J. Wong, C. Ben Hamida, M. Ben Hamida, F. Hentati, L. Kunkel: LGMD 2E in Tunisia is caused by a missense mutation Arg91Leu in b-sarcoglycan. Neuromusc Disord 8: 193-197 (1998).
5. C.G. Bönnemann, R. Passos-Bueno, E.M. McNally, M. Vainzoff, E.de Sá Moreira, S.K. Marie, R.C.M. Pavanello, S. Noguchi, E. Ozawa, M. Zatz, L.M. Kunkel: Genomic screening for b-sarcoglycan mutations: Missense mutations may cause severe limb-girdle muscular dystrophy type 2E (LGMD 2E). Hum Mol Genet 5: 1953-1961 (1996).
6. C.G. Bönnemann, R. Modi, S. Noguchi, Y. Mizuno, M. Yoshida, E. Gussoni, E.M. McNally, D.J. Duggan, C. Angelini, E.P. Hoffman, E. Ozawa, L.M. Kunkel: b-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Nature Genet 11: 266-273 (1995).
7. S. Noguchi, E.M. McNally, K. Ben Othmane, Y. Hagiwara, Y. Mizuno, M. Yoshida, Yamamoto H., C.G. Bönnemann, E. Gussoni, P.H. Denton, T. Kyriakides, L. Middleton, F. Hentati, M. Ben Hamida, I. Nonaka, J. M. Vance, L.M. Kunkel, E. Ozawa: Mutations in the dystrophin-associated protein g-sarcoglycan in chromosome 13 muscular dystrophy. Science 270: 819-822 (1995).