School of Biological Sciences, Monash University, Melbourne, Victoria Australia.
PLoS Genet. 2018 Feb 8;14(2):e1007212. doi: 10.1371/journal.pgen.1007212. eCollection 2018 Feb.
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.
由于蛋白质功能上游触发的补偿性基因表达，纯合突变个体中缺乏突变表型已被确定为遗传补偿。虽然在斑马鱼中已经认识到了这一有趣的过程，但在健康的人类个体中存在纯合功能丧失突变表明补偿可能不仅限于这种模型。骨骼肌α-肌动蛋白的缺失导致杆状体肌病，我们之前已经表明，疾病的病理症状和肌肉性能的降低在斑马鱼反义形态发生素敲低模型中得到了再现。在这里，我们揭示了一个 actc1b 基因的遗传突变体表现出轻微的肌肉缺陷，并且不受 actc1b 靶向形态发生素注射的影响。我们进一步表明，更轻微的表型是由于肌动蛋白同工型的转录上调补偿引起的，这为肌动蛋白肌病的治疗提供了一种新的探索方法。我们的研究结果进一步证明，遗传补偿可能会影响致病突变的外显率。
