Knockout of human muscle genes revealed by large scale whole-exome studies

Large scale whole-exome sequence studies have revealed that a number of individuals from different populations have predicted loss-of-function of different genes due to nonsense, frameshift, or canonical splice-site mutations. Surprisingly, many of these mutations do not apparently show the deleterious phenotypic consequences expected from gene knockout. These homozygous null mutations, when confirmed, can provide insight into human gene function and suggest novel approaches to correct gene dysfunction, as the lack of the expected disease phenotype may reflect the existence of modifier genes that reveal potential therapeutic targets. Human knockouts complement the information derived from mouse knockouts, which are not always good models of human disease. We have examined human knockout datasets searching for genes expressed exclusively or predominantly in striated muscle. A number of well-known muscle genes was found in one or more datasets, including genes coding for sarcomeric myosins, components of the sarcomeric cytoskeleton, sarcoplasmic reticulum and plasma membrane, and enzymes involved in muscle metabolism. The surprising absence of phenotype in some of these human knockouts is critically discussed, focusing on the comparison with the corresponding mouse knockouts.