. Mäkitie RE, Henning P, Jiu Y, Kämpe A, Kogan K, Costantini A, Välimäki VV, Medina-Gomez C, Pekkinen M, Salusky IB, Schalin-Jäntti C, Haanpää MK, Rivadeneira F, Bassett JHD, Williams GR, Lerner UH, Pereira RC, Lappalainen P, Mäkitie O. JBMR Plus. 2021 Jun 7;5(7):e10509. doi: 10.1002/jbm4.10509. PMID: 34258505; PMCID: PMC8260816. Recently, we identified a novel pathogenic variant in ARHGAP25 in a large Finnish family with severe early-onset osteoporosis and prevalent fractures. ARHGAP25 is a regulator of RhoGTPases, which are small signaling molecules implicated in various cellular functions such as cytoskeletal actin modeling and cell migration. RhoGTPases have been shown to have key regulatory roles in bone cell functions, and murine models for different RhoGTPases exhibit severe osteopetrotic phenotypes. ARHGAP25, however, has not been linked to bone metabolism before.The publication reports a novel finding of a genetic defect in RhoGTPase signaling in human skeletal disease. We describe a large, multi-generational Finnish family with an unusual form of autosomal dominant early-onset skeletal fragility with marked propensity to fracture, low bone turnover and low serum phosphate. Using WES, we identified the genetic cause as a novel heterozygous missense mutation in ARHGAP25. Computational modeling predicted the variant to locate near the protein's critical domain and disrupt its normal function and our functional experiments further indicated a role for ARHGAP25 in cytoskeletal dynamics and membrane ruffling and high expression of Arhgap25 in mouse bone tissues. GWASs have further shown a 5'UTR ARGHAP25 variant to associate with BMD and fracture risk. These findings bring new biological insight and expand our understanding of the molecular mechanisms underlying skeletal pathologies