Only the Nterminus fragment of ERM proteins can associate with RhoGDI and activate Rho GTPases signaling, but only full-length FRMD7 will enable this to happen. FRMD7 contains at least three domains: the N-terminus, the FA region and the Cterminus. In our study, we tested the N-terminal FERM domain and a truncated version, but neither interacted with RhoGDI��. This suggests that the mechanism by which FRMD7 exerts its function is different from that of ERM proteins, or possibly that the FA domain is also involved, but this requires further investigation. Meanwhile, it may give some explanation as to why mutations present in different domains eventually lead to the same disease. Our study demonstrated that FRMD7 has the ability to A 943931 dihydrochloride release Rac1 from RhoGDI�� in vitro, where activation of Rac1 Abn-CBD signaling through FRMD7 may be attributable. The release of Rho from RhoGDI�� is an important step allowing the GDPbound form of Rho to be activated by guanine nucleotide exchange factors and to become associated with the membrane. The RhoGDI�� displacement factor, ezrin/radixin/ moesin, also from the FERM family of proteins, induces activation of RhoA in Swiss 3T3 cells. The neurotrophin receptor p75NTR involved in the regulation of axonal elongation can also activate RhoA. Thus, in a similar manner to these proteins, FRMD7 might appear to act as a displacement factor to activate Rac1 signaling, but this needs further investigation. Furthermore, we demonstrated that two missense mutanttype human FRMD7 proteins, which lead to an arginine in the protein 261 loci being substituted for glycine and glycine in the protein 296 loci being substituted for arginine respectively, reduced the ability to associate with RhoGDI��, released less Rac1 from Rac1-RhoGDI�� complex and activated less Rac1. Another mutant-type, c.1003C>T, which results in the arginine of the protein 335 loci to be substituted for a stop codon and leads to a COOH-terminal truncated protein, exhibits a nuclear localization pattern and does not co-localize with the cytoplasmic distribution of F-actin, showed little ability to interact with RhoGDI��, release Rac1 and activate Rac1 signaling. As the Rac1 signaling pathway appears to be involved in the regulation of neurite extension in the developmental stage, mutations of the FRMD7 gene which alter the regulation of Rac1 signaling may be linked to the pathogenesis of idiopathic congenital nystagmus. Three mammalian RhoGDIs have been identified: the ubiquitously expressed RhoGDI1, hematopoietic cell-selective RhoGDI2L and RhoGDI3 which is expressed in the lungs, brain and testes.