PUBLICATION

A Splice Site Mutation in Laminin-alpha2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish

Authors
Gupta, V.A., Kawahara, G., Myers, J.A., Chen, A.T., Hall, T.E., Manzini, M.C., Currie, P.D., Zhou, Y., Zon, L.I., Kunkel, L.M., and Beggs, A.H.
ID
ZDB-PUB-120907-20
Date
2012
Source
PLoS One   7(8): e43794 (Journal)
Registered Authors
Beggs, Alan H., Currie, Peter D., Gupta, Vandana A, Hall, Thomas, Kawahara, Genri, Kunkel, Louis M., Zhou, Yi, Zon, Leonard I.
Keywords
none
MeSH Terms
  • Animals
  • Base Sequence
  • Extracellular Matrix/metabolism
  • Humans
  • Laminin/genetics*
  • Muscle Fibers, Skeletal/metabolism
  • Muscle Fibers, Skeletal/pathology
  • Muscle Fibers, Skeletal/physiology
  • Muscular Dystrophies/genetics*
  • Muscular Dystrophies/pathology
  • Muscular Dystrophies/physiopathology
  • Mutation*
  • RNA Splice Sites/genetics*
  • Zebrafish/genetics*
  • Zebrafish/growth & development*
  • Zebrafish Proteins/genetics*
PubMed
22952766 Full text @ PLoS One
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.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping