Abstract
The filamins are three large cytoskeletal proteins that dynamically cross-link actin and have multiple roles in cellular function and survival. Filamin A (FLNA), encoded by the X-linked gene FLNA, is the most abundant and widely expressed of these filamins. Pathogenic variants in FLNA have been identified in a wide range of human developmental phenotypes known as the X-linked filaminopathies. Gain-of-function variants in FLNA cause a spectrum of sclerosing skeletal disorders that affect patterning and bone mineral density. These disorders are also commonly associated with soft tissue defects that affect multiple organ systems. In this study, we show that inserting a variant that causes frontometaphyseal dysplasia, one of the FLNA-related filaminopathies in humans, into the mouse germline (FlnaC1723W) leads to no obvious effect in the structure or development of the murine skeleton. Detailed characterisation of male mice showed no skeletal phenotype reminiscent of that found in the FLNA-associated skeletal dysplasias. Furthermore, serum markers of osteoblast and osteoclast activity did not differ between male FlnaC1723W/y mice and wildtype littermate controls. We conclude that gain of function filaminopathies are not directly genetically replicable in the mouse.