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  1. Article ; Online: CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

    van Karnebeek, Clara D M / Tarailo-Graovac, Maja / Leen, René / Meinsma, Rutger / Correard, Solenne / Jansen-Meijer, Judith / Prykhozhij, Sergey V / Pena, Izabella A / Ban, Kevin / Schock, Sarah / Saxena, Vishal / Pras-Raves, Mia L / Drögemöller, Britt I / Grootemaat, Anita E / van der Wel, Nicole N / Dobritzsch, Doreen / Roseboom, Winfried / Schomakers, Bauke V / Jaspers, Yorrick R J /
    Zoetekouw, Lida / Roelofsen, Jeroen / Ferreira, Carlos R / van der Lee, Robin / Ross, Colin J / Kochan, Jakub / McIntyre, Rebecca L / van Klinken, Jan B / van Weeghel, Michel / Kramer, Gertjan / Weschke, Bernhard / Labrune, Philippe / Willemsen, Michèl A / Riva, Daria / Garavaglia, Barbara / Moeschler, John B / Filiano, James J / Ekker, Marc / Berman, Jason N / Dyment, David / Vaz, Frédéric M / Wassermann, Wyeth W / Houtkooper, Riekelt H / van Kuilenburg, André B P

    Genetics in medicine : official journal of the American College of Medical Genetics

    2024  Volume 26, Issue 6, Page(s) 101104

    Abstract: Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.!## ...

    Abstract Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.
    Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences.
    Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models.
    Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.
    Language English
    Publishing date 2024-02-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1455352-1
    ISSN 1530-0366 ; 1098-3600
    ISSN (online) 1530-0366
    ISSN 1098-3600
    DOI 10.1016/j.gim.2024.101104
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Deficiency of perforin and hCNT1, a novel inborn error of pyrimidine metabolism, associated with a rapidly developing lethal phenotype due to multi-organ failure.

    Pérez-Torras, Sandra / Mata-Ventosa, Aida / Drögemöller, Britt / Tarailo-Graovac, Maja / Meijer, Judith / Meinsma, Rutger / van Cruchten, Arno G / Kulik, Wim / Viel-Oliva, Albert / Bidon-Chanal, Axel / Ross, Colin J / Wassermann, Wyeth W / van Karnebeek, Clara D M / Pastor-Anglada, Marçal / van Kuilenburg, André B P

    Biochimica et biophysica acta. Molecular basis of disease

    2019  Volume 1865, Issue 6, Page(s) 1182–1191

    Abstract: Pyrimidine nucleotides are essential for a vast number of cellular processes and dysregulation of pyrimidine metabolism has been associated with a variety of clinical abnormalities. Inborn errors of pyrimidine metabolism affecting enzymes in the ... ...

    Abstract Pyrimidine nucleotides are essential for a vast number of cellular processes and dysregulation of pyrimidine metabolism has been associated with a variety of clinical abnormalities. Inborn errors of pyrimidine metabolism affecting enzymes in the pyrimidine de novo and degradation pathway have been identified but no patients have been described with a deficiency in proteins affecting the cellular import of ribonucleosides. In this manuscript, we report the elucidation of the genetic basis of the observed uridine-cytidineuria in a patient presenting with fever, hepatosplenomegaly, persistent lactate acidosis, severely disturbed liver enzymes and ultimately multi-organ failure. Sequence analysis of genes encoding proteins directly involved in the metabolism of uridine and cytidine showed two variants c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in SLC28A1, encoding concentrative nucleotide transporter 1 (hCNT1). Functional analysis showed that these variants affected the three-dimensional structure of hCNT1, altered glycosylation and decreased the half-life of the mutant proteins which resulted in impaired transport activity. Co-transfection of both variants, mimicking the trans disposition of c.1528C > T (p.R510C) and c.1682G > A (p.R561Q) in the patient, significantly impaired hCNT1 biological function. Whole genome sequencing identified two pathogenic variants c.50delT; p.(Leu17Argfs*34) and c.853_855del; p.(Lys285del) in the PRF1 gene, indicating that our patient was also suffering from Familial Hemophagocytic Lymphohistiocytosis type 2. The identification of two co-existing monogenic defects might have resulted in a blended phenotype. Thus, the clinical presentation of isolated hCNT1 deficiency remains to be established.
    MeSH term(s) Fatal Outcome ; Humans ; Infant ; Infant, Newborn ; Male ; Membrane Transport Proteins/deficiency ; Membrane Transport Proteins/genetics ; Multiple Organ Failure/genetics ; Multiple Organ Failure/metabolism ; Perforin/deficiency ; Perforin/genetics ; Phenotype ; Purine-Pyrimidine Metabolism, Inborn Errors/genetics ; Purine-Pyrimidine Metabolism, Inborn Errors/metabolism ; Pyrimidines/metabolism
    Chemical Substances Membrane Transport Proteins ; Pyrimidines ; cif nucleoside transporter ; Perforin (126465-35-8) ; pyrimidine (K8CXK5Q32L)
    Language English
    Publishing date 2019-01-15
    Publishing country Netherlands
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-260X ; 1879-2596 ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbadis.2019.01.013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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