The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura. A clinical, biochemical and in silico study

Ilaria Lazzareschi, Stefano Mastrangelo, Raimondo De Cristofaro, Stefano Lancellotti, Flora Peyvandi, Maria Teresa Pagliari, Andrea Cairo, Safwat Abdel-Azeim, Edrisse Chermak, Luigi Cavallo, Romina Oliva

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

11 Citazioni (Scopus)

Abstract

ongenital 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.
Lingua originaleEnglish
pagine (da-a)51-62-62
Numero di pagine12
RivistaThrombosis and Haemostasis
Volume115
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • ADAMTS-13
  • Congenital thrombotic thrombocytopenic purpura
  • von Willebrand factor

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