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

Handle URI:
http://hdl.handle.net/10754/575523
Title:
The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura
Authors:
Lancellotti, S.; Peyvandi, F.; Pagliari, M.; Cairo, A.; Abdel-Azeim, Safwat ( 0000-0001-8611-1251 ) ; Chermak, Edrisse ( 0000-0002-2716-5724 ) ; Lazzareschi, I.; Mastrangelo, S.; Cavallo, Luigi ( 0000-0002-1398-338X ) ; Oliva, R.; De Cristofaro, R.
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.
KAUST Department:
KAUST Catalysis Center (KCC)
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
Issue Date:
13-Aug-2015
DOI:
10.1160/TH15-02-0119
Type:
Article
ISSN:
0340-6245
Additional Links:
http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH15-02-0119
Appears in Collections:
Articles; KAUST Catalysis Center (KCC)

Full metadata record

DC FieldValue Language
dc.contributor.authorLancellotti, S.en
dc.contributor.authorPeyvandi, F.en
dc.contributor.authorPagliari, M.en
dc.contributor.authorCairo, A.en
dc.contributor.authorAbdel-Azeim, Safwaten
dc.contributor.authorChermak, Edrisseen
dc.contributor.authorLazzareschi, I.en
dc.contributor.authorMastrangelo, S.en
dc.contributor.authorCavallo, Luigien
dc.contributor.authorOliva, R.en
dc.contributor.authorDe Cristofaro, R.en
dc.date.accessioned2015-08-23T10:27:42Zen
dc.date.available2015-08-23T10:27:42Zen
dc.date.issued2015-08-13en
dc.identifier.citationThe D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura 2015, 115 (1) Thrombosis and Haemostasisen
dc.identifier.issn0340-6245en
dc.identifier.doi10.1160/TH15-02-0119en
dc.identifier.urihttp://hdl.handle.net/10754/575523en
dc.description.abstractCongenital 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.en
dc.language.isoenen
dc.publisherSchattauer GmbHen
dc.relation.urlhttp://www.schattauer.de/index.php?id=1214&doi=10.1160/TH15-02-0119en
dc.rightsThis article is not an exact copy of the original published article in Thrombosis and Haemostasis. The definitive publisher-authenticated version of Lancellotti, S., F. Peyvandi, M. Pagliari, A. Cairo, S. Abdel-Azeim, E. Edrisse Chermak, I. Lazzareschi et al. "The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura." Thromb Haemost 115, no. 1 (2015). is available online at:http://www.schattauer.de/index.php?id=1214&doi=10.1160/TH15-02-0119.en
dc.subjectvon Willebrand factoren
dc.subjectADAMTS-13en
dc.subjectcongenital thrombotic thrombocytopenic purpuraen
dc.titleThe D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpuraen
dc.typeArticleen
dc.contributor.departmentKAUST Catalysis Center (KCC)en
dc.identifier.journalThrombosis and Haemostasisen
dc.eprint.versionPost-printen
dc.contributor.institutionCenter for Haemorrhagic and Thrombotic Diseases, Department of Medical Sciences, Catholic University School of Medicine, Rome, Italyen
dc.contributor.institutionAngelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, IRCCS Maggiore Hospital, Mangiagalli, Regina Elena Foundation and University of Milan, Milan, Italyen
dc.contributor.institutionInstitute of Pediatrics, Catholic University School of Medicine, Rome, Italyen
dc.contributor.institutionDepartment of Sciences and Technologies, University “Parthenope” of Naples, Naples, Italyen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorAbdel-Azeim, Safwaten
kaust.authorChermak, Edrisseen
kaust.authorCavallo, Luigien
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