Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Faciogenital dysplasia (FGDY), also known as Aarskog-Scott syndrome, is an X-linked developmental disorder characterized by disproportionately short stature and by facial, skeletal, and urogenital anomalies. Molecular genetic analyses mapped FGDY to chromosome Xp11.21. To clone this gene, YAC clones spanning an FGDY-specific translocation breakpoint were isolated. An isolated cDNA, FGD1, is disrupted by the breakpoint, and FGD1 mutations cosegregate with the disease. FGD1 codes for a 961 amino acid protein that has strong homology to Rho/Rac guanine nucleotide exchange factors (GEFs), contains a cysteine-rich zinc finger-like region, and, like the RasGEF mSos, contains two potential SH3-binding sites. These results provide compelling evidence that FGD1 is responsible for FGDY and suggest that FGD1 is a Rho/RacGEF involved in mammalian development.
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PMID:Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. 795 31

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with the most severe pathology in the T lymphocytes and platelets. The disease arises from mutations in the gene encoding the WAS protein. T lymphocytes of affected males with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that the WAS protein could regulate its organization. We show here that WAS protein interacts with a member of the Rho family of GTPases, Cdc42. This interaction, which is guanosine 5'-triphosphate (GTP)-dependent, was detected in cell lysates, in transient transfections and with purified recombinant proteins. A weaker interaction was also detected with Rac1 using WAS protein from cell lysates. It was also found that different mutant WAS proteins from three affected males retained their ability to interact with Cdc42 and that the level of expression of the WAS protein in these mutants was only 2-5% of normal. Taken together these data suggest that the WAS protein might function as a signal transduction adaptor downstream of Cdc42, and in affected males, the cytoskeletal abnormalities may result from a defect in Cdc42 signaling.
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PMID:Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42. 864 25

Faciogenital dysplasia (FGDY; MIM 305400), or Aarskog syndrome, is an X-linked developmental disorder that adversely affects the formation of specific skeletal structures including elements of the face, the cervical vertebrae, and the distal extremities. FGD1, the gene responsible for faciogenital dysplasia, encodes a guanine nucleotide exchange factor that specifically activates Cdc42, a member of the Rho (Ras homology) family of p21 GTPases. By activating Cdc42, FGD1 stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling and migration, and through Cdc42, FGD1 also activates the stress-activated protein kinase/c-Jun N-terminal kinase signaling cascade, a pathway that regulates cell growth and differentiation. Here, we report a detailed characterization of the genomic organization of the FGD1 gene. The FGD1 gene is composed of 18 exons that range in size from 31 to 1240 bp. These exons span over 51 kb of genomic DNA within region Xp11.21. Flanking intronic sequences and the sequence of the 5' and 3' untranslated regions were determined to facilitate the detection of FGDY patient mutations. 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.
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PMID:Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene. 926 45

Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment. Although it is present in approximately 0.15-0.3% of males, most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown. Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase-activating protein (rhoGAP). By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.
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PMID:Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. 958 72

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.
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PMID:PAK3 mutation in nonsyndromic X-linked mental retardation. 973 25

Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.
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PMID:Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. 1043 59

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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PMID:Isolation, characterization, and mapping of the mouse and human Fgd2 genes, faciogenital dysplasia (FGD1; Aarskog syndrome) gene homologues. 1045 11

FGD1 gene mutations result in faciogenital dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42. 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. Previous work shows that FGD1 is the founding member of a family of related genes including the mouse Fgd2 gene and the rat Frabin gene. Here, we report on the isolation, characterization, and mapping of the mouse Fgd3 gene, a new and novel member of the FGD1 gene family. Fgd3 cDNA encodes a 733-amino-acid protein with a predicted mass of 81 kDa. Fgd3 and FGD1 share a high degree of sequence identity that spans >560 contiguous amino acid residues. Like FGD1, Fgd3 contains adjacent RhoGEF and pleckstrin homology (PH) domains, a second carboxy-terminal PH domain, and a distinctive FYVE domain. Together, these domains appear to form a canonical core structure for FGD1 family members. In addition, compared to other FGD1 family members, Fgd3 contains different structural regions that may be involved in distinct signaling interactions. Microinjection studies show that Fgd3 stimulates fibroblasts to form filopodia, actin microspikes formed upon the stimulation of Cdc42. Fgd3 transcripts are present in several diverse tissues and during mouse embryogenesis, suggesting a developmentally regulated pattern of expression and a potential role in embryonic development. Genetic linkage and radiation hybrid mapping data show that Fgd3 and the human FGD3 ortholog map to syntenic regions of murine chromosome 13 and human chromosome 9q22, respectively. We conclude that Fgd3 is a new and novel member of the FGD1 family of RhoGEF proteins.
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PMID:Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue. 1072 17

FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog syndrome), an X-linked developmental disorder that adversely affects the formation of multiple skeletal structures. To further define the role of FGD1 in skeletal development, we examined its expression in developing mouse embryos and correlated this pattern with FGDY skeletal defects. In this study, we show that Fgd1, the mouse FGD1 ortholog, is initially expressed during the onset of ossification during embryogenesis. Fgd1 is expressed in regions of active bone formation in the trabeculae and diaphyseal cortices of developing long bones. The onset of Fgd1 expression correlates with the expression of bone sialo-protein, a protein specifically expressed in osteoblasts at the onset of matrix mineralization; an analysis of serial sections shows that Fgd1 is expressed in tissues containing calcified and mineralized extracellular matrix. 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. Postnatally, Fgd1 is expressed more broadly in skeletal tissue with expression in the perichondrium, resting chondrocytes, and joint capsule fibroblasts. 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. The observed pattern of Fgd1 expression correlates with FGDY skeletal manifestations and provides an embryologic basis for the prevalence of observed skeletal defects. The observation that the induction of Fgd1 expression coincides with the initiation of ossification strongly suggests that FGD1 signaling plays a role in ossification and bone formation; it also suggests that FGD1 signaling does not play a role in the earlier phases of skeletogenesis. With the observation that FGD1 mutations result in the skeletal dysplasia FGDY, accumulated data indicate that FGD1 signaling plays a critical role in ossification and skeletal development.
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PMID:Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome). 1090 77

Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterised by short stature and multiple facial, limb and genital abnormalities. A gene, FGD1, altered in a patient with AAS phenotype, has been identified and found to encode a protein with homology to Rho/Rac guanine nucleotide exchange factors (Rho/Rac GEF). However, since this original report on identification of a mutated FGD1 gene in an AAS patient, no additional mutations in the FGD1 gene have been described. We analysed 13 independent patients with clinical diagnosis of AAS. One patient presented a mutation that results in a nucleotide change in exon 10 of the FGD1 gene (G2559>A) substituting a Gln for Arg in position 610. The mutation was found to segregate with the AAS phenotype in affected males and carrier females in the family of this patient. 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. The same residue is often mutated in the Bruton's tyrosine kinase (Btk) gene in patients with an X-linked agammaglobulinemia. The Arg610Gln mutation represents the first case of a mutation in the PH domain of the FGD1 gene and additional evidence that mutations in PH domains can be associated to human diseases.
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PMID:A mutation in the pleckstrin homology (PH) domain of the FGD1 gene in an Italian family with faciogenital dysplasia (Aarskog-Scott syndrome). 1093 May 71


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