Abstract
FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42. FGD1 gene mutations result in faciogenital dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. Database searches show that the Caenorhabditis elegans genome contains an FGD1 homologue. Since C. elegans genes often have multiple vertebrate homologues, we hypothesized the existence of multiple mammalian FGD1-related sequences. Here we report the use of degenerate PCR to isolate and characterize the mouse and human Fgd2 genes, new members of the FGD1 gene family. Fgd2 cDNA encodes a 727-amino-acid protein with a predicted mass of 82 kDa. Fgd2 and FGD1 share a high degree of sequence identity that spans >560 contiguous amino acid residues. Fgd2, like FGD1, contains adjacent RhoGEF and PH domains, a second carboxy-terminal PH domain, and a distinctive FYVE domain. Genomic PCR studies indicate some degree of conserved gene structure between Fgd2 and FGD1. Fgd2 transcripts are present in several diverse tissues and during mouse embryogenesis, suggesting a role in embryonic development. Genetic linkage and radiation hybrid mapping data show that Fgd2 and the human FGD2 ortholog map to syntenic regions of murine chromosome 17 and human chromosome 6p21.2, respectively. The observation that all FGD1 gene family members contain equivalent signaling domains and a conserved structural organization strongly suggests that these signaling domains form a canonical core structure for members of the FGD1 family of RhoGEF proteins.
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