Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein

The lack of a mutant phenotype in homozygous mutant individuals' due to compensatory gene expression triggered upstream of protein function has been identified as genetic compensation. Whilst this intriguing process has been recognized in zebrafish, the presence of homozygous loss of function m...

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Bibliographic Details
Published in:PLoS genetics 2018-02, Vol.14 (2), p.e1007212-e1007212
Main Authors: Sztal, Tamar E, McKaige, Emily A, Williams, Caitlin, Ruparelia, Avnika A, Bryson-Richardson, Robert J
Format: Article
Language:English
Subjects:
Actin
Antisense RNA
Biology and Life Sciences
Compensation
Danio rerio
Funding
Gene expression
Gene mutation
Genetic aspects
Genomes
Medicine and Health Sciences
Muscle function
Muscular diseases
Muscular dystrophy
Musculoskeletal system
Mutation
Myopathy
Nemaline myopathy
Phenotypes
Physiological aspects
Proteins
Research and Analysis Methods
Transcription
Vertebrates
Zebrafish
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Summary:The lack of a mutant phenotype in homozygous mutant individuals' due to compensatory gene expression triggered upstream of protein function has been identified as genetic compensation. Whilst this intriguing process has been recognized in zebrafish, the presence of homozygous loss of function mutations in healthy human individuals suggests that compensation may not be restricted to this model. Loss of skeletal α-actin results in nemaline myopathy and we have previously shown that the pathological symptoms of the disease and reduction in muscle performance are recapitulated in a zebrafish antisense morpholino knockdown model. Here we reveal that a genetic actc1b mutant exhibits mild muscle defects and is unaffected by injection of the actc1b targeting morpholino. We further show that the milder phenotype results from a compensatory transcriptional upregulation of an actin paralogue providing a novel approach to be explored for the treatment of actin myopathy. Our findings provide further evidence that genetic compensation may influence the penetrance of disease-causing mutations.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1007212