help button home button Am J Pathol Epitomics, Inc.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fanin, M.
Right arrow Articles by Angelini, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fanin, M.
Right arrow Articles by Angelini, C.
(American Journal of Pathology. 2003;163:1929-1936.)
© 2003 American Society for Investigative Pathology

Loss of Calpain-3 Autocatalytic Activity in LGMD2A Patients with Normal Protein Expression

Marina Fanin*, Anna Chiara Nascimbeni*, Luigi Fulizio*, Carlo Pietro Trevisan*, Marija Meznaric-Petrusa{dagger} and Corrado Angelini*

From the Department of Neurological and Psychiatric Sciences,*University of Padova, Padova, Italy, and the Institute of Anatomy,{dagger}University of Ljubljana, Ljubljana, Slovenia

The diagnosis of limb girdle muscular dystrophy (LGMD) type 2A (due to mutations in the gene encoding for calpain-3) is currently based on protein analysis, but mutant patients with normal protein expression have also been identified. In this study we investigated 150 LGMD patients with normal calpain-3 protein expression, identified gene mutations by an allele-specific polymerase chain reaction test, and analyzed the mutant calpain-3 catalytic activity. Four different mutations were found in eight patients (5.5%): a frame-shifting deletion (550 A del) and three missense (R490Q, R489Q, R490W). Patients with normal calpain-3 protein expression on Western blot are a considerable proportion (20%) of our total LGMD2A population. While in control muscle the calpain-3 Ca++-dependent autocatalytic activity was evident within 5 minutes and was prevented by ethylene diaminetetraacetic acid, in all mutant patient samples the protein was not degraded, indicating that the normal autocatalytic function had been lost. By this new functional test, we show that conventional protein diagnosis fails to detect some mutant proteins, and prove the pathogenetic role of R490Q, R489Q, R490W missense mutations. We suggest that these mutations impair protein activity by affecting interdomain protein interaction, or reduce autocatalytic activity by lowering the Ca++ sensitivity.




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
R. M. Murphy and G. D. Lamb
Endogenous Calpain-3 Activation Is Primarily Governed by Small Increases in Resting Cytoplasmic [Ca2+] and Is Not Dependent on Stretch
J. Biol. Chem., March 20, 2009; 284(12): 7811 - 7819.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
E. J. Groen, R. Charlton, R. Barresi, L. V. Anderson, M. Eagle, J. Hudson, M. S. Koref, V. Straub, and K. M. D. Bushby
Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A
Brain, December 1, 2007; 130(12): 3237 - 3249.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
M Fanin, L Nardetto, A C Nascimbeni, E Tasca, M Spinazzi, R Padoan, and C Angelini
Correlations between clinical severity, genotype and muscle pathology in limb girdle muscular dystrophy type 2A
J. Med. Genet., October 1, 2007; 44(10): 609 - 614.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
R. M. Murphy, C. A. Goodman, M. J. McKenna, J. Bennie, M. Leikis, and G. D. Lamb
Calpain-3 is autolyzed and hence activated in human skeletal muscle 24 h following a single bout of eccentric exercise
J Appl Physiol, September 1, 2007; 103(3): 926 - 931.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
M Fanin, A C Nascimbeni, and C Angelini
Screening of calpain-3 autolytic activity in LGMD muscle: a functional map of CAPN3 gene mutations
J. Med. Genet., January 1, 2007; 44(1): 38 - 43.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
I. Kramerova, E. Kudryashova, B. Wu, and M. J. Spencer
Regulation of the M-Cadherin-{beta}-Catenin Complex by Calpain 3 during Terminal Stages of Myogenic Differentiation
Mol. Cell. Biol., November 15, 2006; 26(22): 8437 - 8447.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
M. Fanin, A. C. Nascimbeni, L. Fulizio, M. Spinazzi, P. Melacini, and C. Angelini
Generalized Lysosome-Associated Membrane Protein-2 Defect Explains Multisystem Clinical Involvement and Allows Leukocyte Diagnostic Screening in Danon Disease
Am. J. Pathol., April 1, 2006; 168(4): 1309 - 1320.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
A. Saenz, F. Leturcq, A. M. Cobo, J. J. Poza, X. Ferrer, D. Otaegui, P. Camano, M. Urtasun, J. Vilchez, E. Gutierrez-Rivas, et al.
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene
Brain, April 1, 2005; 128(4): 732 - 742.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I. Kramerova, E. Kudryashova, J.G. Tidball, and M. J. Spencer
Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro
Hum. Mol. Genet., July 1, 2004; 13(13): 1373 - 1388.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2003 by the American Society for Investigative Pathology.