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European Journal of Human Genetics :... Apr 2015
Topics: Dwarfism; Face; Genetic Diseases, X-Linked; Genetic Testing; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male; Polymorphism, Genetic; Sensitivity and Specificity
PubMed: 25227149
DOI: 10.1038/ejhg.2014.178 -
International Journal of Clinical... Sep 2012This paper reports the treatment and 12-year follow-up of a patient 7 years old who had been diagnosed with Aarskog-Scott syndrome. The patient had a history of...
This paper reports the treatment and 12-year follow-up of a patient 7 years old who had been diagnosed with Aarskog-Scott syndrome. The patient had a history of premature multiple tooth loss, vertical dimension loss and severe dentoalveolar discrepancy. Orthopedic and orthodontic rehabilitation treatments were performed to improve the patient's esthetic, functional and psychological condition. How to cite this article: Closs LQ, Tovo M, Dias C, Corradi DP, Vargas IA. Aarskog-Scott Syndrome: A Review and Case Report. Int J Clin Pediatr Dent 2012;5(3):209-212.
PubMed: 25206170
DOI: 10.5005/jp-journals-10005-1168 -
Indian Pediatrics Apr 2012Aarskog-Scott syndrome is transmitted as an X-linked trait and affects males. We report a 10-year-old boy presenting with complaints of increased temper tantrums,...
Aarskog-Scott syndrome is transmitted as an X-linked trait and affects males. We report a 10-year-old boy presenting with complaints of increased temper tantrums, demanding behavior, grandiose ideas, over familiarity, abusive assaultive behavior and tobacco abuse. On examination, patient had most of the physical characteristics of Aarskog-Scott Syndrome. He also had global developmental delay and attention deficit hyperactivity disorder. This is the first case report of Aarskog Scott syndrome combined with mania.
Topics: Attention Deficit Disorder with Hyperactivity; Bipolar Disorder; Child; Dwarfism; Face; Genetic Diseases, X-Linked; Genitalia, Male; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Male
PubMed: 22565081
DOI: No ID Found -
The Journal of Clinical Investigation Nov 2011Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects...
Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients.
Topics: Animals; Bone Development; Disease Models, Animal; Dwarfism; Enzyme Activation; Face; Female; Gene Knock-In Techniques; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Mutation; Osteoblasts; Proteins; cdc42 GTP-Binding Protein; p38 Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase Kinase Kinase 11
PubMed: 21965325
DOI: 10.1172/JCI59041 -
Molecular and Cellular Biology Nov 2011Podosomes are dynamic actin-rich adhesion plasma membrane microdomains endowed with extracellular matrix-degrading activities. In aortic endothelial cells, podosomes are...
The Aarskog-Scott syndrome protein Fgd1 regulates podosome formation and extracellular matrix remodeling in transforming growth factor β-stimulated aortic endothelial cells.
Podosomes are dynamic actin-rich adhesion plasma membrane microdomains endowed with extracellular matrix-degrading activities. In aortic endothelial cells, podosomes are induced by transforming growth factor β (TGF-β), but how this occurs is largely unknown. It is thought that, in endothelial cells, podosomes play a role in vessel remodeling and/or in breaching anatomical barriers. We demonstrate here that, in bovine aortic endothelial cells, that the Cdc42-specific guanine exchange factor (GEF) Fgd1 is expressed and regulated by TGF-β to induce Cdc42-dependent podosome assembly. Within 15 min of TGF-β stimulation, Fgd1, but none of the other tested Cdc42 GEFs, undergoes tyrosine phosphorylation, associates with Cdc42, and translocates to the subcortical cytoskeleton via a cortactin-dependent mechanism. Small interfering RNA-mediated Fgd1 knockdown inhibits TGF-β-induced Cdc42 activation. Fgd1 depletion also reduces podosome formation and associated matrix degradation and these defects are rescued by reexpression of Fgd1. Although overexpression of Fgd1 does not promote podosome formation per se, it enhances TGF-β-induced matrix degradation. Our results identify Fgd1 as a TGF-β-regulated GEF and, as such, the first GEF to be involved in the process of cytokine-induced podosome formation. Our findings reveal the involvement of Fgd1 in endothelial cell biology and open up new avenues to study its role in vascular pathophysiology.
Topics: Actins; Animals; Aorta; Blood Vessels; Cattle; Cortactin; Dwarfism; Endothelial Cells; Extracellular Matrix; Face; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; RNA Interference; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; cdc42 GTP-Binding Protein
PubMed: 21911474
DOI: 10.1128/MCB.05474-11 -
European Journal of Human Genetics :... Nov 2011
Topics: Dwarfism; Face; Genetic Diseases, X-Linked; Genitalia, Male; Guanine Nucleotide Exchange Factors; Hand Deformities, Congenital; Heart Defects, Congenital; Humans; Mutation
PubMed: 21654724
DOI: 10.1038/ejhg.2011.108 -
Developmental Dynamics : An Official... Aug 2000FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42; FGD1 mutations result in Faciogenital Dysplasia (FGDY, Aarskog...
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.
Topics: 3T3 Cells; Animals; Blotting, Northern; Bone Diseases, Developmental; Bone and Bones; Cells, Cultured; Face; Genetic Linkage; Genitalia; Guanine Nucleotide Exchange Factors; Humans; Immunoblotting; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mutation; Phenotype; Protein Biosynthesis; Proteins; RNA; Reverse Transcriptase Polymerase Chain Reaction; Syndrome; Transfection; Tumor Cells, Cultured; X Chromosome
PubMed: 10906777
DOI: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1015>3.0.CO;2-F -
Archives of Disease in Childhood Oct 1998To test the hypothesis that overall intelligence quotient (IQ) is decreased in patients with Aarskog syndrome.
AIM
To test the hypothesis that overall intelligence quotient (IQ) is decreased in patients with Aarskog syndrome.
METHODS
21 boys under 17 years of age with a confirmed clinical diagnosis of Aarskog syndrome were assessed using the Griffiths mental development scales and the British ability scales.
RESULTS
IQ ranged from 68 to 128 and followed a normal distribution.
CONCLUSION
This study does not support the hypothesis that Aarskog syndrome is associated with a lowering of mean IQ.
Topics: Adolescent; Child; Child, Preschool; Facies; Genitalia, Male; Hand Deformities, Congenital; Humans; Infant; Intellectual Disability; Intelligence; Intelligence Tests; Male; Syndrome
PubMed: 9875050
DOI: 10.1136/adc.79.4.359 -
Human Genetics Oct 1995A Taq1 polymorphism, located in intron 4 of the faciogenital dysplasia (FGD1) gene, the gene responsible for Aarskog syndrome, is described. FGD1 encodes a putative...
A Taq1 polymorphism, located in intron 4 of the faciogenital dysplasia (FGD1) gene, the gene responsible for Aarskog syndrome, is described. FGD1 encodes a putative Rho/Rac guanine nucleotide exchange factor involved in mammalian morphogenesis. The identification of an intragenic polymorphism will facilitate the accurate carrier detection of individuals at risk for Aarskog syndrome.
Topics: Abnormalities, Multiple; Base Sequence; Deoxyribonucleases, Type II Site-Specific; Facial Bones; Humans; Molecular Sequence Data; Polymerase Chain Reaction; Polymorphism, Genetic; Urogenital Abnormalities; X Chromosome
PubMed: 7557980
DOI: 10.1007/BF00191816 -
Journal of Medical Genetics May 1992
Topics: Adult; Child; Estonia; Face; Hand Deformities, Congenital; Humans; Male; Scrotum; Sex Chromosome Aberrations; Syndrome; X Chromosome
PubMed: 1583665
DOI: 10.1136/jmg.29.5.349