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    The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura

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    Type
    Article
    Authors
    Lancellotti, S.
    Peyvandi, F.
    Pagliari, M.
    Cairo, A.
    Abdel-Azeim, Safwat cc
    Chermak, Edrisse cc
    Lazzareschi, I.
    Mastrangelo, S.
    Cavallo, Luigi cc
    Oliva, R.
    De Cristofaro, R.
    KAUST Department
    Chemical Science Program
    KAUST Catalysis Center (KCC)
    KAUST Solar Center (KSC)
    Physical Science and Engineering (PSE) Division
    Date
    2017-11-22
    Online Publication Date
    2017-11-22
    Print Publication Date
    2016-01
    Permanent link to this record
    http://hdl.handle.net/10754/575523
    
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    Abstract
    Congenital thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy, inherited with autosomal recessive mode as a dysfunction or severe deficiency of ADAMTS-13 (A Disintegrin And Metalloprotease with ThromboSpondin 1 repeats Nr. 13), caused by mutations in the ADAMTS-13 gene. About 100 mutations of the ADAMTS-13 gene were identified so far, although only a few characterised by in vitro expression studies. A new Asp to Gly homozygous mutation at position 173 of ADAMTS-13 sequence was identified in a family of Romanian origin, with some members affected by clinical signs of TTP. In two male sons, this mutation caused a severe (< 3 %) deficiency of ADAMTS-13 activity and antigen level, associated with periodic thrombocytopenia, haemolytic anaemia and mild mental confusion. Both parents, who are cousins, showed the same mutation in heterozygous form. Expression studies of the mutant ADAMTS-13, performed in HEK293 cells, showed a severe decrease of the enzyme’s activity and secretion, although the protease was detected inside the cells. Molecular dynamics found that in the D173G mutant the interface area between the metalloprotease domain and the disintegrin-like domain significantly decreases during the simulations, while the proline-rich 20 residues linker region (LR, 285–304) between them undergoes extensive conformational changes. Inter-domain contacts are also significantly less conserved in the mutant compared to the wild-type. Both a decrease of the inter-domain contacts along with a substantial conformational rearrangement of LR interfere with the proper maturation and folding of the mutant ADAMTS-13, thus impairing its secretion.
    Citation
    The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura 2015, 115 (1) Thrombosis and Haemostasis
    Publisher
    Schattauer GmbH
    Journal
    Thrombosis and Haemostasis
    DOI
    10.1160/TH15-02-0119
    Additional Links
    http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH15-02-0119
    ae974a485f413a2113503eed53cd6c53
    10.1160/TH15-02-0119
    Scopus Count
    Collections
    Articles; Physical Science and Engineering (PSE) Division; Chemical Science Program; KAUST Catalysis Center (KCC); KAUST Solar Center (KSC)

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