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Gene Review

FGD1  -  FYVE, RhoGEF and PH domain containing 1

Homo sapiens

Synonyms: AAS, FGDY, FYVE, RhoGEF and PH domain-containing protein 1, Faciogenital dysplasia 1 protein, MRXS16, ...
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Disease relevance of FGD1

  • Fgd1 protein is specifically expressed in cultured osteoblast and osteoblast-like cells including MC3T3-E1 cells and human osteosarcoma cells but not in other mesodermal cells; immunohistochemical studies confirm the presence of Fgd1 protein in mouse calvarial cells [1].
  • Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene [2].
  • Mutations of the FGD1 gene are responsible for a significant proportion of patients with Aarskog-Scott syndrome (AAS), an X-linked disorder characterized by short stature, brachydactyly, urogenital abnormalities, and a typical dysmorphic facial appearance [3].
  • MK enriched by elutriation, which eliminated the MK progenitors, were suspended in culture with serum from either normal donors (NABS) or patients with aplastic anemia (AAS) [4].
  • This patient had no neck pain, no neurologic symptoms or signs, and had AAS of 8 mm [5].

Psychiatry related information on FGD1

  • FGD1 mutations were not associated with severe mental retardation [6].
  • Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott syndrome due to a novel FGD1 gene mutation (R408Q) [3].
  • Data from these studies show clearly that exposure to high doses of multiple AAS during adolescent development can predispose animals to intense bouts of aggressive behavior during young adulthood [7].
  • The hypothesis tested by the study was that the use of AAS induces a wide range of psychological side effects whose impact and emergence is dependent upon the severity of the abuse [8].
  • Psychometric instruments were applied to all athletes in specific time intervals, dependent to the AAS abusers' regimens, providing us with a final psychological profile that was to be compared to the pre-study profile [8].

High impact information on FGD1

  • Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor [9].
  • Molecular genetic analyses mapped FGDY to chromosome Xp11.21 [9].
  • To understand more proximal events in the reductive activation of PA-824, we examined mutants that were wild-type for both FGD1 and F420 and found that, although these mutants had acquired high-level resistance to PA-824 (and another nitroimidazo-oxazine), they retained sensitivity to CGI-17341 (and a related nitroimidazo-oxazole) [10].
  • We have confirmed that resistance to PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) is most commonly mediated by loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor F420, which together provide electrons for the reductive activation of this class of molecules [10].
  • FGD1 mutations result in Faciogenital Dysplasia (FGDY), an X-linked human disease that affects skeletal formation and embryonic morphogenesis [11].

Chemical compound and disease context of FGD1

  • In conclusion, the AAS is more sensitive than the PAS to the early stages of hepatic encephalopathy [12].
  • Serum arsenic concentrations of persons suffering from renal failure and undergoing hemodialysis treatment (n = 85) and of healthy controls (n = 25) were determined by hydride-generation AAS technique after microwave digestion [13].
  • The concentration of Zn, Cd and Se in unseparated tissues and epithelial and stromal fractions of normal prostate gland, BPH and prostatic carcinomas of different histological grading were determined by flameless AAS [14].
  • Factor analysis yielded a 2-factor solution for the AAS (Acknowledgement of Alcohol/Drug Problems; Positive Alcohol Expectancies) and a 4-factor solution for the APS (Satisfaction with Self; Cynicism/Pessimism; Impulsivity; Risk-Taking) [15].

Biological context of FGD1

  • Fgd1, the mouse FGD1 ortholog, is expressed in regions of active bone formation within osteoblasts and in the osteoblast-like cell line MC3T3-E1, a finding consistent with its role in skeletal formation [16].
  • The FGD1 gene is composed of 18 exons that range in size from 31 to 1240 bp [17].
  • By way of Cdc42, FGD1 regulates the actin cytoskeleton and activates the c-Jun N-terminal kinase signaling cascade to regulate cell growth and differentiation [18].
  • Based on these data, we conclude that fgd-1 is the C.elegans homolog of the human FGD1 gene, a new member of the FGD1-related family of RhoGEF genes, and that fgd-1 plays a critical role in excretory cell morphogenesis and cellular organization [19].
  • Database searches show that the Caenorhabditis elegans genome contains an FGD1 homologue [20].

Anatomical context of FGD1

  • RESULTS: Here, we show that the microinjection of FGD1 and Vav into Swiss 3T3 fibroblasts induces the polymerization of actin and the assembly of clustered integrin complexes [21].
  • Mutations to the FGD1 gene result in a human developmental disorder affecting specific skeletal structures, including elements of the face, cervical vertebrae and distal extremities [21].
  • The data indicate that Fgd1 is expressed in a variety of regions of incipient and active endochondral and intramembranous ossification including the craniofacial bones, vertebrae, ribs, long bones and phalanges [1].
  • Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule fibroblasts [1].
  • However, expression of the 7B FGD1 is weak and restricted in the testis and salivary gland [22].

Associations of FGD1 with chemical compounds

  • A mutant FGD1 protein, FGD1(SA), in which both of the critical serine residues in the DSGPsiXS motif have been replaced by alanines, does not interact with FWD1/beta-TrCP and exhibits increased stability [23].
  • FGD1 encodes a putative Rho/Rac guanine nucleotide exchange factor involved in mammalian morphogenesis [24].
  • Insertion of each novel exon results in production of a premature termination codon, respectively, and the predicted proteins generated from them have only a proline-rich domain and an incomplete DH domain which potentially compete with the wild type of FGD1 [22].
  • In contrast, the FYVE-finger and PH2 domains do not appear to direct the localization of Fgd1 or the activation of Cdc42 [16].
  • Direct measurement of lead and cadmium in blood and urine by electrothermal atomic absorption spectrometry with deuterium background correction (D2-AAS) is prone to severe matrix and spectral interferences [25].

Other interactions of FGD1

  • Analyses show that FGD1 transcripts are differentially spliced; in brain and placenta an alternatively spliced form of the FGD1 transcript removes part of the Cdc42GEF domain to encode a null Cdc42 activator [17].
  • Morphological changes induced by wild-type FGD1 (FGD1(WT)) are reduced by the co-expression of SCF(FWD1/beta-TrCP) whereas those induced by FGD1(SA) are not affected [23].
  • We suggest that FGD1 analysis may be adequate in ADHD patients who exhibit dysmorphic features suggestive of AAS, also in the absence of the full phenotypical spectrum [3].
  • Interestingly, Arg-610 is located within one of the two pleckstrin homology (PH) domains of the FGD1 gene and it corresponds to a highly conserved residue which has been involved in InsP binding in PH domains of other proteins [26].

Analytical, diagnostic and therapeutic context of FGD1

  • Comparative sequence analyses show that fgd-1 and FGD1 share a similar structural organization and a high degree of sequence identity throughout shared signaling domains [19].
  • To characterize the FGD1, we investigated its expression by RT-PCR and Southern blot analysis in normal tissues [22].
  • Here, we report the effect of ligation of cortactin's SH3 domain by the Fgd1 SH3-BD on actin polymerization in vitro [27].
  • The new method can also be considered a simple, effective interface between HPLC and flame AAS [28].
  • Therefore, the 32P-postlabelling assay, described by Blommaert and Saris (Nucleic Acids Res., 1995, 23, 1300-1306), to detect the major adducts Pt-GG and Pt-AG has substantially been improved and compared with ELISA and AAS [29].


  1. Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). Gorski, J.L., Estrada, L., Hu, C., Liu, Z. Dev. Dyn. (2000) [Pubmed]
  2. Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Lebel, R.R., May, M., Pouls, S., Lubs, H.A., Stevenson, R.E., Schwartz, C.E. Clin. Genet. (2002) [Pubmed]
  3. Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott syndrome due to a novel FGD1 gene mutation (R408Q). Orrico, A., Galli, L., Buoni, S., Hayek, G., Luchetti, A., Lorenzini, S., Zappella, M., Pomponi, M.G., Sorrentino, V. Am. J. Med. Genet. A (2005) [Pubmed]
  4. Terminal cytoplasmic maturation of human megakaryocytes in vitro. Straneva, J.E., Goheen, M.P., Hui, S.L., Bruno, E., Hoffman, R. Exp. Hematol. (1986) [Pubmed]
  5. Sudden death from cord compression associated with atlanto-axial instability in rheumatoid arthritis. A case report. Yaszemski, M.J., Shepler, T.R. Spine. (1990) [Pubmed]
  6. Phenotypic and molecular characterisation of the Aarskog-Scott syndrome: a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Orrico, A., Galli, L., Cavaliere, M.L., Garavelli, L., Fryns, J.P., Crushell, E., Rinaldi, M.M., Medeira, A., Sorrentino, V. Eur. J. Hum. Genet. (2004) [Pubmed]
  7. Adolescent anabolic steroid use and aggressive behavior in golden hamsters. Melloni, R.H., Ferris, C.F. Ann. N. Y. Acad. Sci. (1996) [Pubmed]
  8. Psychiatric side effects induced by supraphysiological doses of combinations of anabolic steroids correlate to the severity of abuse. Pagonis, T.A., Angelopoulos, N.V., Koukoulis, G.N., Hadjichristodoulou, C.S. Eur. Psychiatry (2006) [Pubmed]
  9. Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Pasteris, N.G., Cadle, A., Logie, L.J., Porteous, M.E., Schwartz, C.E., Stevenson, R.E., Glover, T.W., Wilroy, R.S., Gorski, J.L. Cell (1994) [Pubmed]
  10. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Manjunatha, U.H., Boshoff, H., Dowd, C.S., Zhang, L., Albert, T.J., Norton, J.E., Daniels, L., Dick, T., Pang, S.S., Barry, C.E. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. Fgd1, the Cdc42 GEF responsible for Faciogenital Dysplasia, directly interacts with cortactin and mAbp1 to modulate cell shape. Hou, P., Estrada, L., Kinley, A.W., Parsons, J.T., Vojtek, A.B., Gorski, J.L. Hum. Mol. Genet. (2003) [Pubmed]
  12. Attention dysfunction in cirrhotic patients: an inquiry on the role of executive control, attention orienting and focusing. Amodio, P., Schiff, S., Del Piccolo, F., Mapelli, D., Gatta, A., Umiltà, C. Metabolic brain disease. (2005) [Pubmed]
  13. Essential trace elements in humans. Serum arsenic concentrations in hemodialysis patients in comparison to healthy controls. Mayer, D.R., Kosmus, W., Pogglitsch, H., Mayer, D., Beyer, W. Biological trace element research. (1993) [Pubmed]
  14. Zinc, cadmium and selenium concentrations in separated epithelium and stroma from prostatic tissues of different histology. Feustel, A., Wennrich, R., Dittrich, H. Urol. Res. (1987) [Pubmed]
  15. Diagnostic accuracy and factor structure of the AAS and APS scales of the MMPI-2. Clements, R., Heintz, J.M. Journal of personality assessment. (2002) [Pubmed]
  16. Fgd1, the Cdc42 guanine nucleotide exchange factor responsible for faciogenital dysplasia, is localized to the subcortical actin cytoskeleton and Golgi membrane. Estrada, L., Caron, E., Gorski, J.L. Hum. Mol. Genet. (2001) [Pubmed]
  17. Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene. Pasteris, N.G., Buckler, J., Cadle, A.B., Gorski, J.L. Genomics (1997) [Pubmed]
  18. Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue. Pasteris, N.G., Nagata, K., Hall, A., Gorski, J.L. Gene (2000) [Pubmed]
  19. The Caenorhabditis elegans homolog of FGD1, the human Cdc42 GEF gene responsible for faciogenital dysplasia, is critical for excretory cell morphogenesis. Gao, J., Estrada, L., Cho, S., Ellis, R.E., Gorski, J.L. Hum. Mol. Genet. (2001) [Pubmed]
  20. Isolation, characterization, and mapping of the mouse and human Fgd2 genes, faciogenital dysplasia (FGD1; Aarskog syndrome) gene homologues. Pasteris, N.G., Gorski, J.L. Genomics (1999) [Pubmed]
  21. Faciogenital dysplasia protein (FGD1) and Vav, two related proteins required for normal embryonic development, are upstream regulators of Rho GTPases. Olson, M.F., Pasteris, N.G., Gorski, J.L., Hall, A. Curr. Biol. (1996) [Pubmed]
  22. Novel alternative splicing of human faciogenital dysplasia 1 gene. Yanagi, K., Kaname, T., Chinen, Y., Naritomi, K. Congenital anomalies. (2004) [Pubmed]
  23. The FWD1/beta-TrCP-mediated degradation pathway establishes a 'turning off switch' of a Cdc42 guanine nucleotide exchange factor, FGD1. Hayakawa, M., Kitagawa, H., Miyazawa, K., Kitagawa, M., Kikugawa, K. Genes Cells (2005) [Pubmed]
  24. An intragenic TaqI polymorphism in the faciogenital dysplasia (FGD1) locus, the gene responsible for Aarskog syndrome. Pasteris, N.G., Gorski, J.L. Hum. Genet. (1995) [Pubmed]
  25. Elimination of matrix and spectral interferences in the measurement of lead and cadmium in urine and blood by electrothermal atomic absorption spectrometry with deuterium background correction. D'Haese, P.C., Lamberts, L.V., Liang, L., Van de Vyver, F.L., De Broe, M.E. Clin. Chem. (1991) [Pubmed]
  26. A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). Orrico, A., Galli, L., Falciani, M., Bracci, M., Cavaliere, M.L., Rinaldi, M.M., Musacchio, A., Sorrentino, V. FEBS Lett. (2000) [Pubmed]
  27. Effect of Fgd1 on cortactin in Arp2/3 complex-mediated actin assembly. Kim, K., Hou, P., Gorski, J.L., Cooper, J.A. Biochemistry (2004) [Pubmed]
  28. Beam injection flame furnace atomic absorption spectrometry: a new flame method. Gáspár, A., Berndt, H. Anal. Chem. (2000) [Pubmed]
  29. Improved 32P-postlabelling assay for the quantification of the major platinum-DNA adducts. Welters, M.J., Maliepaard, M., Jacobs-Bergmans, A.J., Baan, R.A., Schellens, J.H., Ma, J., van der Vijgh, W.J., Braakhuis, B.J., Fichtinger-Schepman, A.M. Carcinogenesis (1997) [Pubmed]
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