A splice site mutation in Laminin-α2 results in a severe muscular dystrophy and growth abnormalities in Zebrafish

Gupta, Vandana A., Kawahara, Genri, Myers, Jennifer A., Chen, Aye T., Hall, Thomas E., Manzini, M. Chiara, Currie, Peter D., Zhou, Yi, Zon, Leonard I., Kunkel, Louis M. and Beggs, Alan H. (2012) A splice site mutation in Laminin-α2 results in a severe muscular dystrophy and growth abnormalities in Zebrafish. PLoS One, 7 8: e43794.1-e43794.9. doi:10.1371/journal.pone.0043794


Author Gupta, Vandana A.
Kawahara, Genri
Myers, Jennifer A.
Chen, Aye T.
Hall, Thomas E.
Manzini, M. Chiara
Currie, Peter D.
Zhou, Yi
Zon, Leonard I.
Kunkel, Louis M.
Beggs, Alan H.
Title A splice site mutation in Laminin-α2 results in a severe muscular dystrophy and growth abnormalities in Zebrafish
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2012-08-27
Year available 2012
Sub-type Article (original research)
DOI 10.1371/journal.pone.0043794
Open Access Status DOI
Volume 7
Issue 8
Start page e43794.1
End page e43794.9
Total pages 9
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Collection year 2012
Language eng
Subject 1100 Agricultural and Biological Sciences
1300 Biochemistry, Genetics and Molecular Biology
2700 Medicine
Abstract Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2). Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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