Isolation, characterization, and mapping of the mouse and human Fgd2 genes, faciogenital dysplasia (FGD1; Aarskog syndrome) gene homologues

FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically a ctivates the Rho GTPase Cdc42. FGD1 gene mutations result in faciogenital d ysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. Database s earches show that the Caenorhabditis elegans genome contains an FGD1 homolo gue. Since C. elegans genes often have multiple vertebrate homologues, we h ypothesized the existence of multiple mammalian FGD1-related sequences. Her e 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 encod es 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 a cid residues. Fgd2, like FGD1, contains adjacent RhoGEF and PH domains, a s econd carboxyterminal 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 mo use embryogenesis, suggesting a role in embryonic development. Genetic link age and radiation hybrid mapping data show that Fgd2 and the human FGD2 ort holog map to syntenic regions of murine chromosome 17 and human chromosome 6p21.2, respectively. The observation that all FGD1 gene family members con tain equivalent signaling domains and a conserved structural organization s trongly suggests that these signaling domains form a canonical core structu re for members of the FGD1 family of RhoGEF proteins. (C) 1999 Academic Pre ss.