SMARCA4 (or BAF190, BRG1) is rather frequently mutated in cancer, and here, the clustering of the mutations is informative. Most of the missense mutations are scattered within the highly conserved ATPase domain and group in interesting ways. A highly penetrant ATPase domain mutation made many years ago, K785R (14), is present in several cancers and suggest that at least some of these could be functioning as dominant negative mutations. Similar mutations have been reported in the homologous Brm protein (SMARCA2); these mutations are less frequent in human cancer, yet far more common in neurologic disease. These human genetic observations therefore indicate that in Brg mutant cancers, targeting the synthetic lethal protein Brm (82) (identified in several studies; see “Paralogous subunit compensation as unique synthetic lethalities”) might lead to neurologic defects. In addition, the combined loss of Brg and Brm has been reported in many cancer cell lines, indicating that resistance might quickly develop when Brm is targeted in a Brg mutant.
