Neurology 2001;56:1472-1481
© 2001 American Academy of Neurology
Articles
The earliest pathologic alterations in dysferlinopathy
Duygu Selcen, MD;,
Gail Stilling, BS; and
Andrew G. Engel, MD
From the Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN.
Address correspondence and reprint requests to Dr. Andrew G. Engel, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Background: Dysferlinopathies are associated with proximal or distal muscular dystrophy. Dysferlin immunolocalizes to the muscle fiber periphery but does not associate with the dystrophin–glycoprotein complex; its function in humans, and the mechanism by which it causes muscle fiber injury, are not known. The authors therefore searched for pathogenetic clues by examining early abnormalities in nonnecrotic muscle fibers in dysferlinopathy. Five dysferlin-deficient patients were investigated. Weakness was distal in two, proximal in one, and both proximal and distal in two. Patient 5 was only mildly affected. Methods: Immunoblot analysis, membrane attack complex (MAC) immunolocalization, and quantitative electron microscopy. Results: In Patients 1 through 4, but not in 5, part or the entire surface of isolated nonnecrotic muscle fibers immunostained for MAC. Quantitative electron microscopy of 175 nonnecrotic muscle fibers revealed one or more of the following: 1) small (0.11 to 1.8 µm) plasmalemmal defects in 64% of fibers; 2) thickened basal lamina over some defects; 3) replacement of the plasma membrane by one to multiple layers of small vesicles in 57% of fibers; 4) papillary projections, frequently disintegrating, in 24 to 36% of fibers in Patients 1 through 4 but absent in fibers of Patient 5; 5) small subsarcolemmal vacuoles, some undergoing exocytosis, in 57% of fibers; and 6) infrequent subsarcolemmal regions containing rough endoplasmic reticulum and abundant free ribosomes. Conclusions: Dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy. MAC activation can participate in but is not an initial or primary event causing muscle fiber injury.
This article has been cited by other articles:
|
|
|
|
 
D. P. Millay, M. Maillet, J. A. Roche, M. A. Sargent, E. M. McNally, R. J. Bloch, and J. D. Molkentin
Genetic Manipulation of Dysferlin Expression in Skeletal Muscle: Novel Insights into Muscular Dystrophy
Am. J. Pathol.,
November 1, 2009;
175(5):
1817 - 1823.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kesari, M. Fukuda, S. Knoblach, R. Bashir, G. A. Nader, D. Rao, K. Nagaraju, and E. P. Hoffman
Dysferlin Deficiency Shows Compensatory Induction of Rab27A/Slp2a That May Contribute to Inflammatory Onset
Am. J. Pathol.,
November 1, 2008;
173(5):
1476 - 1487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nagaraju, R. Rawat, E. Veszelovszky, R. Thapliyal, A. Kesari, S. Sparks, N. Raben, P. Plotz, and E. P. Hoffman
Dysferlin Deficiency Enhances Monocyte Phagocytosis: A Model for the Inflammatory Onset of Limb-Girdle Muscular Dystrophy 2B
Am. J. Pathol.,
March 1, 2008;
172(3):
774 - 785.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Klinge, S. Laval, S. Keers, F. Haldane, V. Straub, R. Barresi, and K. Bushby
From T-tubule to sarcolemma: damage-induced dysferlin translocation in early myogenesis
FASEB J,
June 1, 2007;
21(8):
1768 - 1776.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. L. Washington and S. Ward
FER-1 regulates Ca2+-mediated membrane fusion during C. elegans spermatogenesis
J. Cell Sci.,
June 15, 2006;
119(12):
2552 - 2562.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Wenzel, J. Zabojszcza, M. Carl, S. Taubert, A. Lass, C. L. Harris, M. Ho, H. Schulz, O. Hummel, N. Hubner, et al.
Increased Susceptibility to Complement Attack due to Down-Regulation of Decay-Accelerating Factor/CD55 in Dysferlin-Deficient Muscular Dystrophy
J. Immunol.,
November 1, 2005;
175(9):
6219 - 6225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Sakuta, N. Murakami, Y. Jin, T. Nagai, I. Nonaka, and I. Nishino
Diagnostic Significance of Membrane Attack Complex and Vitronectin in Childhood Dermatomyositis
J Child Neurol,
July 1, 2005;
20(7):
597 - 602.
[Abstract]
[PDF]
|
|
|
|
|
|
|
G Cenacchi, M Fanin, L B De Giorgi, and C Angelini
Ultrastructural changes in dysferlinopathy support defective membrane repair mechanism
J. Clin. Pathol.,
February 1, 2005;
58(2):
190 - 195.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ho, C. M. Post, L. R. Donahue, H. G.W. Lidov, R. T. Bronson, H. Goolsby, S. C. Watkins, G. A. Cox, and R. H. Brown Jr
Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency
Hum. Mol. Genet.,
September 15, 2004;
13(18):
1999 - 2010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kirschner and C. G. Bonnemann
The Congenital and Limb-Girdle Muscular Dystrophies: Sharpening the Focus, Blurring the Boundaries
Arch Neurol,
February 1, 2004;
61(2):
189 - 199.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. J. Lennon, A. Kho, B. J. Bacskai, S. L. Perlmutter, B. T. Hyman, and R. H. Brown Jr.
Dysferlin Interacts with Annexins A1 and A2 and Mediates Sarcolemmal Wound-healing
J. Biol. Chem.,
December 12, 2003;
278(50):
50466 - 50473.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Davis, K. R. Doherty, A. J. Delmonte, and E. M. McNally
Calcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains
J. Biol. Chem.,
June 14, 2002;
277(25):
22883 - 22888.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Matsuda, Y. K. Hayashi, M. Ogawa, M. Aoki, K. Murayama, I. Nishino, I. Nonaka, K. Arahata, and R. H. B. Jr
The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle
Hum. Mol. Genet.,
August 1, 2001;
10(17):
1761 - 1766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
