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Gene Review

Capn3  -  calpain 3

Mus musculus

Synonyms: AI323605, CANP 3, Calcium-activated neutral proteinase 3, Calpain L3, Calpain p94, ...
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Disease relevance of Capn3

  • This enigmatic protease has many unique features among the calpain family and, importantly, mutations in Capn3 have been shown to be responsible for limb girdle muscular dystrophy type 2A [1].
  • Here we demonstrate that the Capn3 activation mechanism is similar to the universal activation of caspases and corresponds to an autolysis within the active site of the protease [1].
  • Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice [2].
  • Unexpectedly, we found that full-length C3 can be overexpressed at high levels in vivo, without toxicity [3].
  • Both types of cataracts showed rapid elevation of calcium, activation of Lp82 and m-calpain, and proteolysis of crystallins [4].

High impact information on Capn3

  • It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles [2].
  • Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases [2].
  • In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations [2].
  • Although LGMD 2A would be a feasible candidate for gene therapy, the reported instability of C3 in vitro raised questions about the potential of obtaining a stable, high-level expression of C3 from a transgene in vivo [3].
  • We have generated transgenic (Tg) mice with muscle-specific overexpression of full-length C3 or C3 isoforms, which arise from alternative splicing, to test whether stable expression of C3 transgenes could occur in vivo [3].

Chemical compound and disease context of Capn3


Biological context of Capn3


Anatomical context of Capn3

  • We undertook a search for substrates in immature muscle cells, as several lines of evidence suggest that Capn3 is mostly in an inactive state in muscle and needs a signal to be activated [1].
  • In this model, Capn3 proteolytic activity leads to disruption of the actin cytoskeleton and disorganization of focal adhesions through cleavage of several endogenous proteins [1].
  • Lp82 was expressed at E9.5 in the lens placode, head ectoderm, and throughout the fiber cells during embryonic lens maturation [10].
  • We observed the presence in testis and ovaries of abundant, novel transcripts of the Capn3 gene arising from the antisense strand of the Pgk1-neomycin cassette [9].
  • Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway [6].

Associations of Capn3 with chemical compounds


Physical interactions of Capn3

  • Thus, the composition of the titin N2A protein complex is altered in MDM by incorporation of CARP and loss of p94/calpain-3 [11].

Regulatory relationships of Capn3

  • Endogenous Lp82 in lens soluble proteins was activated by addition of calcium and caused limited proteolysis of crystallins even in the presence of large amounts of recombinant domain I from the natural calpain inhibitor calpastatin [12].

Other interactions of Capn3

  • Monoclonal antibodies raised against CANP2 reacted almost equally with CANP1 and CANP3 [5].
  • Bidirectional transcriptional activity of the Pgk1 promoter and transmission ratio distortion in Capn3-deficient mice [9].
  • In contrast, muscle mRNA levels for ubiquitin and subunit S5a of the 26S proteasome were unaffected by calpain-3 deficiency [13].
  • Rates of protein synthesis and breakdown, cathepsin activities, and rates of substrate ubiquitination remained stable in muscles from calpain-3 deficient mice [13].

Analytical, diagnostic and therapeutic context of Capn3


  1. Calpain 3 is activated through autolysis within the active site and lyses sarcomeric and sarcolemmal components. Taveau, M., Bourg, N., Sillon, G., Roudaut, C., Bartoli, M., Richard, I. Mol. Cell. Biol. (2003) [Pubmed]
  2. Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice. Richard, I., Roudaut, C., Marchand, S., Baghdiguian, S., Herasse, M., Stockholm, D., Ono, Y., Suel, L., Bourg, N., Sorimachi, H., Lefranc, G., Fardeau, M., Sébille, A., Beckmann, J.S. J. Cell Biol. (2000) [Pubmed]
  3. Stable expression of calpain 3 from a muscle transgene in vivo: immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation. Spencer, M.J., Guyon, J.R., Sorimachi, H., Potts, A., Richard, I., Herasse, M., Chamberlain, J., Dalkilic, I., Kunkel, L.M., Beckmann, J.S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  4. Contribution of calpain Lp82-induced proteolysis to experimental cataractogenesis in mice. Nakamura, Y., Fukiage, C., Shih, M., Ma, H., David, L.L., Azuma, M., Shearer, T.R. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  5. Third form of calcium-activated neutral proteinase from calf brain: purification, partial characterization and comparison of properties with other forms. Malik, M.N., Fenko, M.D., Sheikh, A.M., Kascsak, R.J., Tonna-DeMasi, M.S., Wisniewski, H.M. Biochim. Biophys. Acta (1987) [Pubmed]
  6. Calpain 3 participates in sarcomere remodeling by acting upstream of the ubiquitin-proteasome pathway. Kramerova, I., Kudryashova, E., Venkatraman, G., Spencer, M.J. Hum. Mol. Genet. (2005) [Pubmed]
  7. Diverse mRNA expression patterns of the mouse calpain genes Capn5, Capn6 and Capn11 during development. Dear, T.N., Boehm, T. Mech. Dev. (1999) [Pubmed]
  8. Possible regulation of the conventional calpain system by skeletal muscle-specific calpain, p94/calpain 3. Ono, Y., Kakinuma, K., Torii, F., Irie, A., Nakagawa, K., Labeit, S., Abe, K., Suzuki, K., Sorimachi, H. J. Biol. Chem. (2004) [Pubmed]
  9. Bidirectional transcriptional activity of the Pgk1 promoter and transmission ratio distortion in Capn3-deficient mice. Taveau, M., Stockholm, D., Marchand, S., Roudaut, C., Le Bert, M., Richard, I. Genomics (2004) [Pubmed]
  10. Protein expression patterns for ubiquitous and tissue specific calpains in the developing mouse lens. Reed, N.A., Castellini, M.A., Ma, H., Shearer, T.R., Duncan, M.K. Exp. Eye Res. (2003) [Pubmed]
  11. Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling. Witt, C.C., Ono, Y., Puschmann, E., McNabb, M., Wu, Y., Gotthardt, M., Witt, S.H., Haak, M., Labeit, D., Gregorio, C.C., Sorimachi, H., Granzier, H., Labeit, S. J. Mol. Biol. (2004) [Pubmed]
  12. Lp82 is the dominant form of calpain in young mouse lens. Ma, H., Hata, I., Shih, M., Fukiage, C., Nakamura, Y., Azuma, M., Shearer, T.R. Exp. Eye Res. (1999) [Pubmed]
  13. Down-regulation of genes in the lysosomal and ubiquitin-proteasome proteolytic pathways in calpain-3-deficient muscle. Combaret, L., Béchet, D., Claustre, A., Taillandier, D., Richard, I., Attaix, D. Int. J. Biochem. Cell Biol. (2003) [Pubmed]
  14. Molecular cloning of mouse canp3, the gene associated with limb-girdle muscular dystrophy 2A in human. Richard, I., Beckmann, J.S. Mamm. Genome (1996) [Pubmed]
  15. Highly conserved structure in the promoter region of the gene for muscle-specific calpain, p94. Sorimachi, H., Forsberg, N.E., Lee, H.J., Joeng, S.Y., Richard, I., Beckmann, J.S., Ishiura, S., Suzuki, K. Biol. Chem. (1996) [Pubmed]
  16. Calpain 3 is expressed in astrocytes of rat and Microcebus brain. König, N., Raynaud, F., Feane, H., Durand, M., Mestre-Francès, N., Rossel, M., Ouali, A., Benyamin, Y. J. Chem. Neuroanat. (2003) [Pubmed]
  17. Physiological correlation between glycyrrhizin, glycyrrhizin-binding lipoxygenase and casein kinase II. Shimoyama, Y., Ohtaka, H., Nagata, N., Munakata, H., Hayashi, N., Ohtsuki, K. FEBS Lett. (1996) [Pubmed]
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