A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish

Vandana A Gupta, Genri Kawahara, Jennifer A Myers, Aye T Chen, Thomas Edward Hall, Chiara Manzini, Peter David Currie, Yi Zhou, Leonard I Zon, Louis M Kunkel, Alan H Beggs

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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-alpha2 gene (LAMA2). Laminin-alpha2 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 lama2(cl501/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-alpha2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha2 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.
Original languageEnglish
Article numbere43794
Number of pages9
JournalPLoS ONE
Volume7
Issue number8
DOIs
Publication statusPublished - 2012

Cite this

Gupta, V. A., Kawahara, G., Myers, J. A., Chen, A. T., Hall, T. E., Manzini, C., ... Beggs, A. H. (2012). A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish. PLoS ONE, 7(8), [e43794]. https://doi.org/10.1371/journal.pone.0043794
Gupta, Vandana A ; Kawahara, Genri ; Myers, Jennifer A ; Chen, Aye T ; Hall, Thomas Edward ; Manzini, Chiara ; Currie, Peter David ; Zhou, Yi ; Zon, Leonard I ; Kunkel, Louis M ; Beggs, Alan H. / A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish. In: PLoS ONE. 2012 ; Vol. 7, No. 8.
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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-alpha2 gene (LAMA2). Laminin-alpha2 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 lama2(cl501/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-alpha2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha2 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.",
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Gupta, VA, Kawahara, G, Myers, JA, Chen, AT, Hall, TE, Manzini, C, Currie, PD, Zhou, Y, Zon, LI, Kunkel, LM & Beggs, AH 2012, 'A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish', PLoS ONE, vol. 7, no. 8, e43794. https://doi.org/10.1371/journal.pone.0043794

A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish. / Gupta, Vandana A; Kawahara, Genri; Myers, Jennifer A; Chen, Aye T; Hall, Thomas Edward; Manzini, Chiara; Currie, Peter David; Zhou, Yi; Zon, Leonard I; Kunkel, Louis M; Beggs, Alan H.

In: PLoS ONE, Vol. 7, No. 8, e43794, 2012.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A splice site mutation in laminin-alpha2 results in a severe muscular dystrophy and growth abnormalities in zebrafish

AU - Gupta, Vandana A

AU - Kawahara, Genri

AU - Myers, Jennifer A

AU - Chen, Aye T

AU - Hall, Thomas Edward

AU - Manzini, Chiara

AU - Currie, Peter David

AU - Zhou, Yi

AU - Zon, Leonard I

AU - Kunkel, Louis M

AU - Beggs, Alan H

PY - 2012

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N2 - 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-alpha2 gene (LAMA2). Laminin-alpha2 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 lama2(cl501/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-alpha2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha2 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.

AB - 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-alpha2 gene (LAMA2). Laminin-alpha2 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 lama2(cl501/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-alpha2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-alpha2 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.

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