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  1. Article ; Online: Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency.

    Block, Jana / Rashkova, Christina / Castanon, Irinka / Zoghi, Samaneh / Platon, Jessica / Ardy, Rico C / Fujiwara, Mitsuhiro / Chaves, Beatriz / Schoppmeyer, Rouven / van der Made, Caspar I / Jimenez Heredia, Raul / Harms, Frederike L / Alavi, Samin / Alsina, Laia / Sanchez Moreno, Paula / Ávila Polo, Rainiero / Cabrera-Pérez, Rocío / Kostel Bal, Sevgi / Pfajfer, Laurène /
    Ransmayr, Bernhard / Mautner, Anna-Katharina / Kondo, Ryohei / Tinnacher, Anna / Caldera, Michael / Schuster, Michael / Domínguez Conde, Cecilia / Platzer, René / Salzer, Elisabeth / Boyer, Thomas / Brunner, Han G / Nooitgedagt-Frons, Judith E / Iglesias, Estíbaliz / Deyà-Martinez, Angela / Camacho-Lovillo, Marisol / Menche, Jörg / Bock, Christoph / Huppa, Johannes B / Pickl, Winfried F / Distel, Martin / Yoder, Jeffrey A / Traver, David / Engelhardt, Karin R / Linden, Tobias / Kager, Leo / Hannich, J Thomas / Hoischen, Alexander / Hambleton, Sophie / Illsinger, Sabine / Da Costa, Lydie / Kutsche, Kerstin / Chavoshzadeh, Zahra / van Buul, Jaap D / Antón, Jordi / Calzada-Hernández, Joan / Neth, Olaf / Viaud, Julien / Nishikimi, Akihiko / Dupré, Loïc / Boztug, Kaan

    The New England journal of medicine

    2023  Volume 389, Issue 6, Page(s) 527–539

    Abstract: Background: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) ... ...

    Abstract Background: Increasing evidence links genetic defects affecting actin-regulatory proteins to diseases with severe autoimmunity and autoinflammation, yet the underlying molecular mechanisms are poorly understood. Dedicator of cytokinesis 11 (DOCK11) activates the small Rho guanosine triphosphatase (GTPase) cell division cycle 42 (CDC42), a central regulator of actin cytoskeleton dynamics. The role of DOCK11 in human immune-cell function and disease remains unknown.
    Methods: We conducted genetic, immunologic, and molecular assays in four patients from four unrelated families who presented with infections, early-onset severe immune dysregulation, normocytic anemia of variable severity associated with anisopoikilocytosis, and developmental delay. Functional assays were performed in patient-derived cells, as well as in mouse and zebrafish models.
    Results: We identified rare, X-linked germline mutations in
    Conclusions: Germline hemizygous loss-of-function mutations affecting the actin regulator DOCK11 were shown to cause a previously unknown inborn error of hematopoiesis and immunity characterized by severe immune dysregulation and systemic inflammation, recurrent infections, and anemia. (Funded by the European Research Council and others.).
    MeSH term(s) Animals ; Humans ; Mice ; Actins/genetics ; Actins/metabolism ; Anemia/etiology ; Anemia/genetics ; Disease Models, Animal ; Guanine Nucleotide Exchange Factors/deficiency ; Guanine Nucleotide Exchange Factors/genetics ; Hematopoiesis ; Inflammation/etiology ; Inflammation/genetics ; Zebrafish/genetics ; Zebrafish/metabolism
    Chemical Substances Actins ; CDC42 protein, human (EC 3.6.5.2) ; Cdc42 protein, mouse ; Guanine Nucleotide Exchange Factors
    Language English
    Publishing date 2023-06-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa2210054
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis.

    Ozen, Ahmet / Comrie, William A / Ardy, Rico C / Domínguez Conde, Cecilia / Dalgic, Buket / Beser, Ömer F / Morawski, Aaron R / Karakoc-Aydiner, Elif / Tutar, Engin / Baris, Safa / Ozcay, Figen / Serwas, Nina K / Zhang, Yu / Matthews, Helen F / Pittaluga, Stefania / Folio, Les R / Unlusoy Aksu, Aysel / McElwee, Joshua J / Krolo, Ana /
    Kiykim, Ayca / Baris, Zeren / Gulsan, Meltem / Ogulur, Ismail / Snapper, Scott B / Houwen, Roderick H J / Leavis, Helen L / Ertem, Deniz / Kain, Renate / Sari, Sinan / Erkan, Tülay / Su, Helen C / Boztug, Kaan / Lenardo, Michael J

    The New England journal of medicine

    2017  Volume 377, Issue 1, Page(s) 52–61

    Abstract: Background: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.: Methods: We studied 11 patients with abdominal pain and diarrhea caused by ... ...

    Abstract Background: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
    Methods: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55.
    Results: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation.
    Conclusions: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
    MeSH term(s) CD55 Antigens/blood ; CD55 Antigens/genetics ; Child ; Child, Preschool ; Complement Activation/drug effects ; Complement Activation/genetics ; Complement Inactivating Agents/pharmacology ; Complement System Proteins/metabolism ; Female ; Homozygote ; Humans ; Immunoglobulin A/blood ; Infant ; Intestine, Small/pathology ; Male ; Mutation ; Pedigree ; Protein-Losing Enteropathies/complications ; Protein-Losing Enteropathies/genetics ; Statistics, Nonparametric ; Syndrome ; T-Lymphocytes/metabolism ; Thrombosis/genetics
    Chemical Substances CD55 Antigens ; Complement Inactivating Agents ; Immunoglobulin A ; Complement System Proteins (9007-36-7)
    Language English
    Publishing date 2017-06-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa1615887
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.34: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

    Serwas, Nina K / Hoeger, Birgit / Ardy, Rico C / Stulz, Sigrun V / Sui, Zhenhua / Memaran, Nima / Meeths, Marie / Krolo, Ana / Yüce Petronczki, Özlem / Pfajfer, Laurène / Hou, Tie Z / Halliday, Neil / Santos-Valente, Elisangela / Kalinichenko, Artem / Kennedy, Alan / Mace, Emily M / Mukherjee, Malini / Tesi, Bianca / Schrempf, Anna /
    Pickl, Winfried F / Loizou, Joanna I / Kain, Renate / Bidmon-Fliegenschnee, Bettina / Schickel, Jean-Nicolas / Glauzy, Salomé / Huemer, Jakob / Garncarz, Wojciech / Salzer, Elisabeth / Pierides, Iro / Bilic, Ivan / Thiel, Jens / Priftakis, Peter / Banerjee, Pinaki P / Förster-Waldl, Elisabeth / Medgyesi, David / Huber, Wolf-Dietrich / Orange, Jordan S / Meffre, Eric / Sansom, David M / Bryceson, Yenan T / Altman, Amnon / Boztug, Kaan

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 3106

    Abstract: Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially ... ...

    Abstract Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11
    MeSH term(s) B7-1 Antigen/metabolism ; CTLA-4 Antigen/metabolism ; DNA-Binding Proteins/deficiency ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/immunology ; Gene Knockout Techniques ; Guanine Nucleotide Exchange Factors/deficiency ; Guanine Nucleotide Exchange Factors/genetics ; Guanine Nucleotide Exchange Factors/immunology ; Homeostasis ; Humans ; Jurkat Cells ; Primary Immunodeficiency Diseases/genetics ; T-Lymphocytes/metabolism ; T-Lymphocytes/physiology ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
    Chemical Substances B7-1 Antigen ; CTLA-4 Antigen ; DEF6 protein, human ; DNA-Binding Proteins ; Guanine Nucleotide Exchange Factors ; rab11 protein (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2019-07-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-10812-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Publisher Correction: Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis.

    Serwas, Nina K / Hoeger, Birgit / Ardy, Rico C / Stulz, Sigrun V / Sui, Zhenhua / Memaran, Nima / Meeths, Marie / Krolo, Ana / Petronczki, Özlem Yüce / Pfajfer, Laurène / Hou, Tie Z / Halliday, Neil / Santos-Valente, Elisangela / Kalinichenko, Artem / Kennedy, Alan / Mace, Emily M / Mukherjee, Malini / Tesi, Bianca / Schrempf, Anna /
    Pickl, Winfried F / Loizou, Joanna I / Kain, Renate / Bidmon-Fliegenschnee, Bettina / Schickel, Jean-Nicolas / Glauzy, Salomé / Huemer, Jakob / Garncarz, Wojciech / Salzer, Elisabeth / Pierides, Iro / Bilic, Ivan / Thiel, Jens / Priftakis, Peter / Banerjee, Pinaki P / Förster-Waldl, Elisabeth / Medgyesi, David / Huber, Wolf-Dietrich / Orange, Jordan S / Meffre, Eric / Sansom, David M / Bryceson, Yenan T / Altman, Amnon / Boztug, Kaan

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 4555

    Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

    Abstract An amendment to this paper has been published and can be accessed via a link at the top of the paper.
    Language English
    Publishing date 2019-10-02
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-12454-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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