The Experts below are selected from a list of 1029 Experts worldwide ranked by ideXlab platform

Jean-pierre Fryns - One of the best experts on this subject based on the ideXlab platform.

Lucia Galli - One of the best experts on this subject based on the ideXlab platform.

Alfredo Orrico - One of the best experts on this subject based on the ideXlab platform.

  • clinical utility gene card for aarskog Scott Syndrome faciogenital dysplasia update 2015
    European Journal of Human Genetics, 2015
    Co-Authors: Alfredo Orrico, Lucia Galli, Jill Claytonsmith, Jean-pierre Fryns
    Abstract:

    Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

  • Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015
    European Journal of Human Genetics, 2014
    Co-Authors: Alfredo Orrico, Lucia Galli, Jill Clayton-smith, Jean-pierre Fryns
    Abstract:

    Clinical utility gene card for: Aarskog–Scott Syndrome (faciogenital dysplasia) – update 2015

  • Clinical utility gene card for: Aarskog-Scott Syndrome (faciogenital dysplasia)
    European Journal of Human Genetics, 2011
    Co-Authors: Alfredo Orrico, Lucia Galli, Jill Clayton-smith, Jean-pierre Fryns
    Abstract:

    Medicina Molecolare. Azienda Ospedaliera Universitaria Senese. Siena. Italy. Manchester Academic Health Sciences Centre, St Mary's Hospital, Manchester, UK. Center for Human Genetics, University Hospital Leuven. Herestraat 49 B-3000 Leuven, Belgium. Corresponding author: Alfredo Orrico. Molecular Medicine, Azienda Ospedaliera Universitaria Senese, Policlinico “S. Maria alle Scotte”, Viale Bracci 2, 53100 Siena, Italy. tel/fax: +39 0577 586264. E-mail: a.orrico@ao-siena.toscana.it.

  • Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott Syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1.
    American Journal of Medical Genetics Part A, 2007
    Co-Authors: Armand Bottani, Alfredo Orrico, Lucia Galli, Olivier Karam, Charles-andré Haenggeli, Solène Ferey, Bernard Conrad
    Abstract:

    Faciogenital dysplasia or Aarskog-Scott Syndrome (AAS) is an X-linked disorder characterized by craniofacial, skeletal, and urogenital malformations and short stature. Mutations in the only known causative gene FGD1 are found in about one-fifth of the cases with the clinical diagnosis of AAS. FGD1 is a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42 via its RhoGEF domain. The Cdc42 pathway is involved in skeletal formation and multiple aspects of neuronal development. We describe a boy with typical AAS and, in addition, unilateral focal polymicrogyria (PMG), a feature hitherto unreported in AAS. Sequencing of the FGD1 gene in the index case and his mother revealed the presence of a novel mutation (1396A>G; M466V), located in the evolutionary conserved alpha-helix 4 of the RhoGEF domain. M466V was not found in healthy family members, in >300 healthy controls and AAS patients, and has not been reported in the literature or mutation databases to date, indicating that this novel missense mutation causes AAS, and possibly PMG. Brain cortex malformations such as PMG could be initiated by mutations in the evolutionary conserved RhoGEF domain of FGD1, by perturbing the signaling via Rho GTPases such as Cdc42 known to cause brain malformation.

  • Unusually severe expression of craniofacial features in Aarskog-Scott Syndrome due to a novel truncating mutation of the FGD1 gene.
    American Journal of Medical Genetics Part A, 2006
    Co-Authors: Alfredo Orrico, Lucia Galli, Michela Falciani, M G Obregon, M F De Castro Perez, Vincenzo Sorrentino
    Abstract:

    Aarskog-Scott Syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X-linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described. © 2006 Wiley-Liss, Inc.

Vincenzo Sorrentino - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Report Unusually Severe Expression of Craniofacial Features in Aarskog-Scott Syndrome Due to a Novel Truncating Mutation of the FGD1 Gene
    2007
    Co-Authors: A Orrico, Lucia Galli, Michela Falciani, Vincenzo Sorrentino
    Abstract:

    Aarskog-Scott Syndrome (AAS) is a rare, clinically andgenetically heterogeneous condition characterized by facialdysmorphic features, short stature, brachydactyly, andgenital anomalies. The X-linked form is caused by mutationsof the FGD1 gene. Although clinical manifestations anddiagnostic criteria are well established, diagnosis is notsimple, as the spectrum of phenotypical features may beextremely variable. Here, we report on the clinical andgenetic characterization of a family in which molecularanalyses revealed the inheritance of a novel truncatingmutation of the FDG1 gene (c.945insC) in two affectedbrothers, with one of them displaying unusually severecraniofacial abnormalities. This previously unreported com-binationofanomaliesmight beduetotheoccurrence of twodistinct disorders (AAS and hemifacial microsomia) or mayrepresentanextensionoftheAASphenotypicspectrum.Ourfindings highlight the phenotypic heterogeneity of AAS,supporting the opinion that the FGD1 mutations result in abroadspectrumofseverityand,insomecases,mayexpressaclinical appearance very different than typically described.

  • Unusually severe expression of craniofacial features in Aarskog-Scott Syndrome due to a novel truncating mutation of the FGD1 gene.
    American Journal of Medical Genetics Part A, 2007
    Co-Authors: A Orrico, L Galli, Michela Falciani, M G Obregon, M F De Castro Perez, Vincenzo Sorrentino
    Abstract:

    Aarskog-Scott Syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X-linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described.

  • Unusually severe expression of craniofacial features in Aarskog-Scott Syndrome due to a novel truncating mutation of the FGD1 gene.
    American Journal of Medical Genetics Part A, 2006
    Co-Authors: Alfredo Orrico, Lucia Galli, Michela Falciani, M G Obregon, M F De Castro Perez, Vincenzo Sorrentino
    Abstract:

    Aarskog-Scott Syndrome (AAS) is a rare, clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies. The X-linked form is caused by mutations of the FGD1 gene. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, as the spectrum of phenotypical features may be extremely variable. Here, we report on the clinical and genetic characterization of a family in which molecular analyses revealed the inheritance of a novel truncating mutation of the FDG1 gene (c.945insC) in two affected brothers, with one of them displaying unusually severe craniofacial abnormalities. This previously unreported combination of anomalies might be due to the occurrence of two distinct disorders (AAS and hemifacial microsomia) or may represent an extension of the AAS phenotypic spectrum. Our findings highlight the phenotypic heterogeneity of AAS, supporting the opinion that the FGD1 mutations result in a broad spectrum of severity and, in some cases, may express a clinical appearance very different than typically described. © 2006 Wiley-Liss, Inc.

  • Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott Syndrome due to a novelFGD1 gene mutation (R408Q)
    American Journal of Medical Genetics Part A, 2005
    Co-Authors: Alfredo Orrico, Lucia Galli, Sabrina Buoni, Giuseppe Hayek, Anna Luchetti, Stefania Lorenzini, Michele Zappella, Maria Grazia Pomponi, Vincenzo Sorrentino
    Abstract:

    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. Although mental retardation does not occur significantly in AAS, this condition has been described associated with various degrees of mental impairment and/or behavioral disorders in some patients. In particular, attention deficit hyperactivity disorder (ADHD) is reported as a common characteristic of AAS. However, AAS/ADHD reported patients have been only clinically described, and diagnosis never has been confirmed on molecular basis. We present here a unique case of a 16-years-old patient presenting with ADHD, lower intelligence quotient, and dysmorphic features. Although the clinical features were not completely typical of AAS, genetic analysis demonstrated a novel FGD1 missense mutation (R408Q). The case we report confirms the highly variable expressivity of AAS and first documents that the FGD1 gene may play a role in ADHD susceptibility. 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

  • Attention-deficit/hyperactivity disorder (ADHD) and variable clinical expression of Aarskog-Scott Syndrome due to a novel FGD1 gene mutation (R408Q).
    American journal of medical genetics. Part A, 2005
    Co-Authors: Alfredo Orrico, Lucia Galli, Sabrina Buoni, Giuseppe Hayek, Anna Luchetti, Stefania Lorenzini, Michele Zappella, Maria Grazia Pomponi, Vincenzo Sorrentino
    Abstract:

    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. Although mental retardation does not occur significantly in AAS, this condition has been described associated with various degrees of mental impairment and/or behavioral disorders in some patients. In particular, attention deficit hyperactivity disorder (ADHD) is reported as a common characteristic of AAS. However, AAS/ADHD reported patients have been only clinically described, and diagnosis never has been confirmed on molecular basis. We present here a unique case of a 16-years-old patient presenting with ADHD, lower intelligence quotient, and dysmorphic features. Although the clinical features were not completely typical of AAS, genetic analysis demonstrated a novel FGD1 missense mutation (R408Q). The case we report confirms the highly variable expressivity of AAS and first documents that the FGD1 gene may play a role in ADHD susceptibility. 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. © 2005 Wiley-Liss, Inc.

Edouard M. Bevers - One of the best experts on this subject based on the ideXlab platform.

  • calcium activated and apoptotic phospholipid scrambling induced by ano6 can occur independently of ano6 ion currents
    Cell Death and Disease, 2013
    Co-Authors: Arthur Kmit, Jiraporn Ousingsawat, Nadine J A Mattheij, Birgit L M G Sendengijsbers, Rainer Schreiber, Edouard M. Bevers, Roger Van Kruchten, Johan W M Heemskerk, Karl Kunzelmann
    Abstract:

    Immune cells and platelets maintain plasma membrane phospholipid asymmetry. Upon activation, this asymmetry is disrupted by phospholipid scrambling (PS), which is a major step during activation of immune cells, hemostasis and apoptosis. Anoctamin 6 (Ano6; TMEM16F) causes chloride (Cl−) and cation currents and is required for Ca2+-dependent PS. It is defective in blood cells from patients with Scott Syndrome, a rare bleeding disorder. We examined if Cl− currents and PS are related, whether both processes are Ca2+ dependent, and whether Ca2+-independent scrambling during intrinsic and extrinsic apoptosis is controlled by Ano6. Ca2+ increase by ionomycin activated Ano6 Cl− currents and PS in normal lymphocytes, but not in B-lymphocytes from two different patients with Scott Syndrome. Fas ligand (FasL) did not increase intracellular Ca2+, but activated Cl− currents in normal but not in Scott lymphocytes. Whole-cell currents were inhibited by Cl− channel blockers and by siRNA knockdown of Ano6. In contrast, intrinsic mitochondrial apoptosis by ABT-737 did not induce Cl− currents in lymphocytes. PS was not inhibited by blockers of Ano6 or removal of Cl− ions. Remarkably, Ca2+-independent scrambling due to extrinsic (FasL) or intrinsic (ABT-737) apoptosis was unchanged in Scott cells. We conclude that: (i) Ano6 Cl− currents are activated by increase in cytosolic Ca2+, or Ca2+ independent by stimulation of Fas receptors; (ii) Ca2+-dependent PS induced by Ano6 does not require Cl− currents; (iii) Ca2+-independent PS does not require Ano6; (iv) Ano6 is necessary for Ca2+-dependent PS, but not by increasing intracellular Ca2+.

  • Both TMEM16F-dependent and TMEM16F-independent pathways contribute to phosphatidylserine exposure in platelet apoptosis and platelet activation
    Blood, 2013
    Co-Authors: Roger Van Kruchten, Nadine J A Mattheij, Johan W M Heemskerk, Peter Collins, Frauke Swieringa, Marion A.h. Feijge, Christine Saunders, Jef L. N. Wolfs, Edouard M. Bevers
    Abstract:

    Scott Syndrome, a bleeding disorder caused by defective phospholipid scrambling, has been associated with mutations in the TMEM16F gene. The role of TMEM16F in apoptosis- or agonist-induced phosphatidylserine (PS) exposure was studied in platelets from a Scott Syndrome patient and control subjects. Whereas stimulation of control platelets with the BH3-mimetic ABT737 resulted in two distinct fractions with moderate and high PS exposure, the high PS exposing fraction was markedly delayed in Scott platelets. High, but not moderate PS exposure in platelets was suppressed by chelation of intracellular Ca 2+ , while caspase inhibition completely abolished ABT737-induced PS exposure in both Scott and control platelets. On the other hand, high PS exposure induced by the Ca 2+ -mobilizing agonists convulxin/thrombin fully relied on mitochondrial depolarization, and was virtually absent in Scott platelets. Finally, PS exposure induced by collagen/thrombin was partly affected in Scott platelets, and the residual PS positive fraction was insensitive to inhibition of caspases or mitochondrial depolarization. In conclusion: TMEM16F is not required for, but enhances caspase-dependent PS exposure; convulxin/thrombin-induced PS exposure is entirely dependent on TMEM16F, whereas collagen/thrombin-induced PS exposure results from two distinct pathways, one of which involves mitochondrial depolarization and is mediated by TMEM16F.

  • Compound heterozygosity for 2 novel TMEM16F mutations in a patient with Scott Syndrome.
    Blood, 2011
    Co-Authors: Elisabetta Castoldi, Peter Collins, Patrick Williamson, Edouard M. Bevers
    Abstract:

    To the editor: Loss of transmembrane lipid asymmetry in apoptotic cells or in activated platelets is thought to be catalyzed by a specific membrane protein named phospholipid scramblase.[1][1] Recently, the transmembrane protein TMEM16F was shown to be required for Ca2+-induced lipid scrambling and

  • phospholipid scramblase an update
    FEBS Letters, 2010
    Co-Authors: Edouard M. Bevers, Patrick Williamson
    Abstract:

    The best understood consequence of the collapse of lipid asymmetry is exposure of phosphatidylserine (PS) in the external leaflet of the plasma membrane bilayer, where it is known to serve at least two major functions: providing a platform for development of the blood coagulation cascade and presenting the signal that induces phagocytosis of apoptotic cells. Lipid asymmetry is collapsed by activation of phospholipid scramblase(s) that catalyze bidirectional transbilayer movement of the major classes of phospholipid. The protein corresponding to this activity is not yet known. Observations on cells from patients with Scott Syndrome, a rare hereditary bleeding disorder resulting from impaired lipid scrambling, have shown that there are multiple activation pathways that converge on scramblase activity.

  • Absence of platelet-dependent fibrin formation in a patient with Scott Syndrome
    Thrombosis and haemostasis, 2009
    Co-Authors: Simone J.h. Wielders, Edouard M. Bevers, Peter Collins, Jos L. V. Broers, Hugo Ten Cate, Theo Lindhout
    Abstract:

    To gain insight into the contribution of platelet-dependent thrombin formation in haemostasis and thrombosis, we investigated under flow conditions the haemostatic functions of platelets from a patient with Scott Syndrome. Scott platelets are characterised by a diminished platelet-dependent thrombin generation. Thrombin generation was determined by calibrated automated thrombography and flow-based experiments were performed to reveal collagen-mediated platelet activation and fibrin deposition. Our studies indicate that adherent Scott platelets do not differ from control platelets in the formation of stable platelet aggregates under static and flow conditions. While for adherent control platelets a shape change, e.g. balloon formation, and externalisation of phosphatidylserine (PS) is associated with an increase in intracellular calcium concentration, this is not the case for Scott platelets. The calcium-induced morphological changes in control platelets are accompanied with a diminished recruitment of free flowing platelets. Scott platelets, not showing a calcium-induced shape change, also lost the ability to recruit free flowing platelets. These findings rebut the hypothesis that the mild bleeding tendency of Scott Syndrome patients is due to a preserved adhesive activity of patient’s platelets. Perfusion of tissue factor (TF)-activated control blood over immobilised collagen results in the formation of fibrin fibers that radiate from platelet aggregates. Although platelet aggregates were also observed after perfusion with TF-activated Scott blood, fibrin deposition was not observed. In conclusion, our findings indicate that platelet adhesion and spreading on a collagen matrix in the absence of fibrin formation is sufficient to sustain haemostasis under non-traumatic conditions.