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Mutations in the gene–encoding SERCA1, the fast–twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease

Nature Genetics volume 14, pages 191–194 (1996)Cite this article

Abstract

Brody disease is a rare inherited disorder of skeletal muscle function. Symptoms include exercise-induced impairment of skeletal muscle relaxation, stiffness and cramps. Ca2+ uptake and Ca2+ ATPase activities are reduced in the sarcoplasmic reticulum1–7, leading to the prediction that Brody disease results from defects in the ATP2A1 gene on chromosome 16p12.1–12.2, encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase. A recent search, however, did not reveal any mutations in the ATP2A1 gene in three Brody patients8. We have now associated Brody disease with the autosomal recessive inheritance of three ATP2A1 mutations in two families, suggesting that the disease is genetically heterogeneous. One mutation occurs at the splice donor site of intron 3, while the other two mutations lead to premature stop codons, truncating SERCA1, deleting essential functional domains and raising the intriguing question: how have these Brody patients partially compensated for the functional knockout of a gene product believed to be essential for fast-twitch skeletal muscle relaxation?

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References

  1. Brody, I.A. Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor. New Engl. J. Med. 281, 187–192 (1969).

    Article  CAS  Google Scholar 

  2. Karpati, G., Charuk, J., Carpenter, S., Jablecki, C. & Holland, P. Myopathy caused by a deficiency of Ca2+-adenosine triphosphatase in sarcoplasmic reticulum (Brody's disease). Ann. Neurol. 20, 38–49 (1986).

    Article  CAS  Google Scholar 

  3. Danon, M.J., Karpati, G., Charuk, J. & Holland, P. Sarcoplasmic reticulum adenosine triphosphatase deficiency with probable autosomal dominant inheritance. Neurology 38, 812–815 (1988).

    Article  CAS  Google Scholar 

  4. Taylor, D.J. et al. Ca2+-ATPase deficiency in a patient with an exertional muscle pain syndrome. J. Neurol. Neurosurg. Psychiat. 51, 1425–1433 (1988).

    Article  CAS  Google Scholar 

  5. Wevers, R.A. et al. Ischaemic forearm testing in a patient with Ca2+-ATPase deficiency. J. Inher. Metab. Dis. 15, 423–425 (1992).

    Article  CAS  Google Scholar 

  6. Poels, P.J.E. et al. Exertional rhabdomyolysis in a patient with calcium adenosine triphosphatase deficiency. J. Neurol. Neurosurg. Psychiat. 56, 823–826 (1993).

    Article  CAS  Google Scholar 

  7. Benders, A.A.G.M. et al. Ca2+ homeostasis in Brody's disease. A study in skeletal and cultured muscle cells and the effects of dantrolene and verapamil. J. Clin. Invest. 94, 741–748 (1994).

    Article  CAS  Google Scholar 

  8. Zhang, Y. et al. 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, 415–424 (1995).

    Article  CAS  Google Scholar 

  9. MacLennan, D.H. et al. Fast-twitch and slow-twitch/cardiac Ca2+ ATPase genes map to human chromosome 16 and 12. Som. Cell Mol. Genet. 13, 341–346 (1987).

    Article  CAS  Google Scholar 

  10. Callen, D.F. et al. Integration of transcript and genetic maps of chromosome 16 at near-1-Mb resolution: demonstration of a “hotspot” for recombination at 16p12. Genomics 29, 503–511, (1995).

    Article  CAS  Google Scholar 

  11. MacLennan, D.H., Clarke, D.M., Loo, T.W. & Skerjanc, I. Site-directed mutagenesis of the Ca2+ ATPase of sarcoplasmic reticulum. Acta Physiol. Scand. 146, 141–150 (1992).

    Article  CAS  Google Scholar 

  12. Krawczak, M., Reiss, J. & Cooper, D.N. The mutational spectrum of single base-pair substitutions in messenger RNA splice junctions of human genes — causes and consequences. Hum. Genet. 90, 41–54 (1992).

    Article  CAS  Google Scholar 

  13. Ebashi, S, Endo, M. & Ohtsuki, I. Control of muscle contraction. Quart. Rev. Biophys. 2, 351–384 (1969).

    Article  CAS  Google Scholar 

  14. Brandl, C.J., Green, N.M., Korczak, B. & MacLennan, D.H. Two Ca2+ATPase genes: homologies and mechanistic implication of deduced amino acid sequences. Cell 44, 597–607 (1986).

    Article  CAS  Google Scholar 

  15. Wu, K.-D., Lee, W.-F., Wey, J., Bungard, D. & Lytton, J. Localization and quantification of endoplasmic reticulum Ca2+ ATPase isoform transcripts. Am. J. Physiol. 269, C775–C784 (1995).

    Article  CAS  Google Scholar 

  16. Carafoli, E., Intracellular calcium homeostasis. Annu. Rev. Biochem. 56, 395–433 (1987).

    Article  CAS  Google Scholar 

  17. Lytton, J. & MacLennan, D.H. Molecular cloning of cDNAs from human kidney coding for two alternatively spliced products of the cardiac Ca2+ ATPase gene. J. Biol. Cham. 263, 15024–15031 (1988).

    CAS  Google Scholar 

  18. Burk, S.E., Lytton, J., MacLennan, D.H. & Shull, G.E. cDNA cloning, functional expression and mRNA tissue distribution of a third organellar Ca2+ pump. J. Biol. Chem. 264, 18561–18568 (1989).

    CAS  PubMed  Google Scholar 

  19. Berridge, M.J. Capacitative calcium entry. Biochem. J. 312, 1–11 (1995).

    Article  CAS  Google Scholar 

  20. Reeders, S.T., Hildebrand, C.E. & Sutherland, G.R. Report of the committee on the genetic constitution of chromosome 16. Cytogenet. Cell Genet. 58, 643–685 (1991).

    Article  Google Scholar 

  21. Thompson, A.D. et al. Isolation and characterization of (AC)n microsatellite genetic markers from human chromosome 16. Genomics 13, 402–408 (1992).

    Article  CAS  Google Scholar 

  22. Shen, Y. et al. Dinucleotide repeat polymorphism at the D16S288 locus. Nucl. Acids Res. 19, 5445 (1991).

    Article  CAS  Google Scholar 

  23. Breuning, M.H. et al. Two step procedure for early diagnosis of polycystic kidney disease with polymorphic DNA markers on both sides of the gene. J. Med. Genet. 27, 614–617 (1990).

    Article  CAS  Google Scholar 

  24. Sambrook, J., Fritsch, E.F. & Maniatis, T. in Molecular Cloning: A Laboratory Manual, 2nd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

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Authors and Affiliations

  1. Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, 112 College St., Toronto, Ontario, M5G 1L6, Canada

    Alex Odermatt, Vijay K. Khanna & David H. MacLennan

  2. Department of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, Wassenaarseweg 72, 2300 RA, Leiden, The Netherlands

    Peter E. M. Taschner & Martijn H. Breuning

  3. Department of Neurology, Erasmus University, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands

    Herman F. M. Busch

  4. Montreal Neurological Institute, McGill University, 3801 Rue University, Montreal, Quebec, H3A2B4, Canada

    George Karpati

  5. Departmentof Neuroscience, University of California at San Diego, 550 Washington Street, Suite 221, San Diego, California, 92103, USA

    Charles K. Jablecki

  6. Department of Clinical Genetics, Erasmus University, Dr. Molewaterplein 50, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands

    Martijn H. Breuning

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  1. Alex Odermatt
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  5. George Karpati
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  8. David H. MacLennan
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Correspondence to David H. MacLennan.

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Odermatt, A., Taschner, P., Khanna, V. et al. Mutations in the gene–encoding SERCA1, the fast–twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 14, 191–194 (1996). https://doi.org/10.1038/ng1096-191

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