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Molecular and Cellular Biology, June 1999, p. 4047-4055, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Expression and Functional Characteristics of Calpain 3 Isoforms Generated through Tissue-Specific Transcriptional and Posttranscriptional Events

Muriel Herasse,1 Yasuko Ono,2 Françoise Fougerousse,1 Ei-ichi Kimura,2 Daniel Stockholm,1 Cyriaque Beley,1 Didier Montarras,3 Christian Pinset,3 Hiroyuki Sorimachi,2 Koichi Suzuki,2 Jacques S. Beckmann,1,* and Isabelle Richard1

Généthon, CNRS URA 1922, 91000 Evry,1 and Institut Pasteur, 75015 Paris,3 France, and IMCB, University of Tokyo, Tokyo 113-0032, Japan2

Received 1 December 1998/Returned for modification 22 December 1998/Accepted 3 March 1999

Calpain 3 is a nonlysosomal cysteine protease whose biological functions remain unknown. We previously demonstrated that this protease is altered in limb girdle muscular dystrophy type 2A patients. Preliminary observations suggested that its gene is subjected to alternative splicing. In this paper, we characterize transcriptional and posttranscriptional events leading to alterations involving the NS, IS1, and IS2 regions and/or the calcium binding domains of the mouse calpain 3 gene (capn3). These events can be divided into three groups: (i) splicing of exons that preserve the translation frame, (ii) inclusion of two distinct intronic sequences between exons 16 and 17 that disrupt the frame and would lead, if translated, to a truncated protein lacking domain IV, and (iii) use of an alternative first exon specific to lens tissue. In addition, expression of these isoforms seems to be regulated. Investigation of the proteolytic activities and titin binding abilities of the translation products of some of these isoforms clearly indicated that removal of these different protein segments affects differentially the biochemical properties examined. In particular, removal of exon 6 impaired the autolytic but not fodrinolytic activity and loss of exon 16 led to an increased titin binding and a loss of fodrinolytic activity. These results are likely to impact our understanding of the pathophysiology of calpainopathies and the development of therapeutic strategies.

* Corresponding author. Mailing address: Généthon, 1 rue de l'Internationale, 91000 Evry, France. Phone: 33-1 69 47 29 38. Fax: 33-1 60 77 86 98. E-mail: beckmann{at}genethon.fr.

Molecular and Cellular Biology, June 1999, p. 4047-4055, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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