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.

Genome editing reveals reproductive and developmental dependencies on specific types of vitellogenin in zebrafish (Danio rerio)

“…The lack of a mutant phenotype in Hm mutant individuals due to compensatory gene expression triggered upstream of protein function is known as “genetic compensation” and this phenomenon has been encountered in gene editing studies of a wide range of model organisms. As examples, Marschang et al () related the normal development and lack of mutant phenotypes in LDL receptor‐related protein 1b ( LRP1b )‐deficient mutant mice to functional compensation by LRP1 , and Sztal et al () found that a genetic actin1b ( actc1b ) zebrafish mutant exhibits only mild muscle defects and is unaffected by injection of an actc1b ‐targeting morpholino due to compensatory transcriptional upregulation of an actin paralog in the same fish. In the present study, compensatory increases in relative levels of total Vtg protein attributable to upregulation of Vtg7 protein in F4 Hm vtg1 ‐KO eggs offset only about half of the decrease in total Vtg protein attributable to KO of vtg1 , 4 , and 5 (Figure a).…”

Genome editing reveals reproductive and developmental dependencies on specific types of vitellogenin in zebrafish (Danio rerio)

“…The lack of a mutant phenotype in Hm mutant individuals due to compensatory gene expression triggered upstream of protein function is known as ‘genetic compensation’ and this phenomenon has been encountered in gene editing studies of a wide range of model organisms. As examples, Marschang et al (2004) related the normal development and lack of mutant phenotypes in LDL receptor-related protein 1b ( LRP1b )-deficient mutant mice to functional compensation by LRP1, and Sztal et al (2018) found that a genetic actin1b ( actc1b ) zebrafish mutant exhibits only mild muscle defects and is unaffected by injection of an actc1b -targeting morpholino due to compensatory transcriptional upregulation of an actin paralog in the same fish. In the present study, compensatory increases in relative levels of total Vtg protein attributable to upregulation of Vtg7 protein in F4 Hm vtg1 -KO eggs offset only about half of the decrease in total Vtg protein attributable to KO of vtg1, 4 and 5 ( Fig 5A ).…”

SLC2A knockout mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects

“…One mechanism of biological robustness is transcriptional adaptation [52,53]. This mechanism is triggered by mRNA degradation products and is believed to act via sequence similarity [54,55]. Since Slc2a10 is a member of a large family of facilitative glucose transporter proteins harboring a high sequence similarity, this mechanism is plausible [56].…”