filaminopathy skeletal phenotypes are not due to an osteoblast autonomous loss-of-function.

Mutations in , which encodes the cytoskeletal protein FLNA, cause a spectrum of sclerosing skeletal dysplasias. Although many of these genetic variants are recurrent and cluster within the gene, the pathogenic mechanism that underpins the development of these skeletal phenotypes is unknown. To determine if the skeletal dysplasia in -related conditions is due to a cell-autonomous loss-of-function localising to osteoblasts and/or osteocytes, we utilised mouse models to conditionally remove from this cellular lineage. was conditionally knocked out from mature osteocytes using the promoter driven Cre-recombinase expressing mouse, as well as the committed osteoblast lineage using the Cre or -Cre expressing lines. We measured skeletal parameters with μCT and histological methods, as well as gene expression in the mineralised skeleton. We found no measureable differences between the conditional knockout mice, and their control littermate counterparts. Moreover, all of the conditional knockout mice, developed and aged normally. From this we concluded that the skeletal dysplasia phenotype associated with pathogenic variants in is not caused by a cell-autonomous loss-of-function in the osteoblast-osteocyte lineage, adding more evidence to the hypothesis that these phenotypes are due to gain-of-function in