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

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article numbere1007212
Number of pages15
JournalPLoS Genetics
Volume14
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Cite this

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title = "Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein",
abstract = "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.",
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Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein. / Sztal, Tamar E.; McKaige, Emily A; Williams, Caitlin; Ruparelia, Avnika A.; Bryson-Richardson, Robert J.

In: PLoS Genetics, Vol. 14, No. 2, e1007212, 01.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - McKaige, Emily A

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AU - Bryson-Richardson, Robert J.

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