Ca 2+ ATPase Phospholamban, Sarcolipin Brody Disease Publications Cardiomyopathy Ca2+ Release Channel MH/CCD Ca2+ Binding Proteins OMIM Brody myopathy OMIM SERCA1 OMIM SLN						SERCA1 and Sarcolipin in Brody Disease Each muscle contraction requires the entry of Ca2+ into the muscle cytoplasm, while relaxation requires removal of the activating Ca2+, making Ca2+ regulation of muscle one of the most extensive activities in the human body. It is not surprising, therefore, that proteins involved in Ca2+ regulation, when mutated, can lead to a variety of skeletal and cardiac muscle diseases that are related to defects in Ca2+ regulation. One of these diseases is Brody disease (BD), an inherited disorder of skeletal muscle function that is characterized by exercise-induced contracture brought on by delayed relaxation. We studied three human BD families where the disease is clearly autosomal recessive and found premature stop codons in the ATP2A1 gene, encoding SERCA1 (homozygous in two; compound heterozygous in the other), leading to truncation and complete loss of SERCA1 function. While these studies show that defects in ATP2A1 are a probable causal of recessive forms of BD, they raise the interesting question of how humans lacking SERCA1, which normally accounts for 99% of SERCA isoforms in fast-twitch muscle, are able to function at all. We are creating an ATP2A1 knockout mouse to provide material for determination of how abnormal Ca2+ regulatory systems can be compensated for in muscle disease. Brody disease also occurs with autosomal dominant inheritance. We have shown that ATP2A1 is not the causal gene in these cases. A current goal is to determine the causal gene for autosomal dominant BD. We have investigated the possibility that SLN might be mutated to become a stronger inhibitor of SERCA1 in these families. We were, however, unable to find any mutations in the SLN gene in several Brody families.
Ca 2+ ATPase Phospholamban, Sarcolipin Brody Disease Top of Page Cardiomyopathy Ca2+ Release Channel MH/CCD Ca2+ Binding Proteins OMIM Brody myopathy OMIM SERCA1 OMIM SLN						Brody Disease Publications Odermatt, A., Becker, S., Khanna, V.K., Kurzydlowski, K., Leisner, E., Pette, D. and MacLennan, D.H. (1998) Sarcolipin regulates the activity of SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase. Journal of Biological Chemistry 273(in press) MacLennan, D.H., Loke, J. and Odermatt, A. (1997) The role of genes encoding sarcoplasmic reticulum proteins in malignant hyperthermia, central core disease and Brody disease, in Calcium as a Cellular Regulator (Carafoli, E. and Klee, C.) Oxford University Press New York MacLennan, D.H., Rice, W.J. and Odermatt, A. (1997) Structure-function analysis of the Ca2+ binding and translocation domain of SERCA1 and the role of Brody disease of the ATP2A1 gene encoding SERCA1. New York Acad. Sci. (in press) Odermatt, A., Taschner, P.E.M., Khanna, V.K., Busch, H.F.M., Karpati, G., Jablecki, C.K., Breuning, M.H. and MacLennan, D.H. (1996) Mutations in the gene encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nature Genetics 14191-4 Zhang, Y.L., Fujii, J., Phillips, M.S., Chen, H.-S., Karpati, G., Yee, W.-C., Schrank, B., Cornblath, D.R., Boylan, K.B. and MacLennan, D.H. (1995) Characterization of cDNA and genomic DNA encoding SERCA1, the Ca2+ ATPase of human fast-twitch skeletal muscle sarcoplasmic reticulum and its elimination as a candidate gene for Brody disease in three patients. Genomics 30(3):415-24 Callen, D.F., Baker, E., Lane, S., Nancarrow, J., Thompson, A., Whitmore, S.A., MacLennan, D.H., Berger, R., Cherif, D., Jarvela, I. and et al. (1991) Regional mapping of the Batten disease locus (CLN3) to human chromosome 16p12. American Journal of Human Genetics 49(6):1372-7 Korczak, B., Zarain-Herzberg, A., Brandl, C.J., Ingles, C.J., Green, N.M. and MacLennan, D.H. (1988) Structure of the rabbit fast-twitch skeletal muscle Ca2+-ATPase gene. Journal of Biological Chemistry 263(10):4813-9 MacLennan, D.H., Brandl, C.J., Champaneria, S., Holland, P.C., Powers, V.E. and Willard, H.F. (1987) Fast-twitch and slow-twitch/cardiac Ca2+ ATPase genes map to human chromosomes 16 and 12. Somatic Cell & Molecular Genetics 13(4):341-6
Brody Disease Top of Page Publications Revised 1998Apr09