Advanced

Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency.

Assink, Karin; Schiphorst, Rikke; Allford, Sarah; Karpman, Diana LU ; Etzioni, Amos; Brichard, Bénédicte; Van De Kar, Nicole; Monnens, Leo and Van Den Heuvel, Lambertus (2003) In Kidney International 63(6). p.1995-1999
Abstract
Background. The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP.



Methods. Blood for DNA analysis was collected from six unrelated... (More)
Background. The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP.



Methods. Blood for DNA analysis was collected from six unrelated TTP families, consisting of nine patients from four different countries, and was screened for mutations in the ADAMTS 13 gene. This gene spans 29 exons encompassing ~37 kb. Conventional techniques of DNA extraction, polymerase chain reaction (PCR), and direct cycle sequencing were used.



Results. Eight novel ADAMTS 13 mutations are presented. Half of the total number of mutant ADAMTS13 alleles are amino acid substitutions. The disease-causing mutations are spread over the gene. The pathogenicity of the individual mutations is based upon their predicted effect on the ADAMTS13 protein and segregation in family members. Although most of the patients (seven out of nine) had symptoms during the neonatal period, they were in a remarkably good condition. Only one of the nine patients had a decreased glomerular filtration rate (GFR) with proteinuria and hematuria. Another patient had epileptic seizures.



Conclusion. We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Kidney International
volume
63
issue
6
pages
1995 - 1999
publisher
Nature Publishing Group
external identifiers
  • wos:000182781900003
  • pmid:12753286
  • scopus:0037513434
ISSN
1523-1755
DOI
language
English
LU publication?
yes
id
72df28fe-723a-4ac9-ba67-c9a0c54f5676 (old id 113886)
alternative location
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12753286&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
date added to LUP
2007-07-19 11:25:14
date last changed
2018-06-10 04:40:05
@article{72df28fe-723a-4ac9-ba67-c9a0c54f5676,
  abstract     = {Background. The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP.<br/><br>
<br/><br>
Methods. Blood for DNA analysis was collected from six unrelated TTP families, consisting of nine patients from four different countries, and was screened for mutations in the ADAMTS 13 gene. This gene spans 29 exons encompassing ~37 kb. Conventional techniques of DNA extraction, polymerase chain reaction (PCR), and direct cycle sequencing were used.<br/><br>
<br/><br>
Results. Eight novel ADAMTS 13 mutations are presented. Half of the total number of mutant ADAMTS13 alleles are amino acid substitutions. The disease-causing mutations are spread over the gene. The pathogenicity of the individual mutations is based upon their predicted effect on the ADAMTS13 protein and segregation in family members. Although most of the patients (seven out of nine) had symptoms during the neonatal period, they were in a remarkably good condition. Only one of the nine patients had a decreased glomerular filtration rate (GFR) with proteinuria and hematuria. Another patient had epileptic seizures.<br/><br>
<br/><br>
Conclusion. We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions.},
  author       = {Assink, Karin and Schiphorst, Rikke and Allford, Sarah and Karpman, Diana and Etzioni, Amos and Brichard, Bénédicte and Van De Kar, Nicole and Monnens, Leo and Van Den Heuvel, Lambertus},
  issn         = {1523-1755},
  language     = {eng},
  number       = {6},
  pages        = {1995--1999},
  publisher    = {Nature Publishing Group},
  series       = {Kidney International},
  title        = {Mutation analysis and clinical implications of von Willebrand factor-cleaving protease deficiency.},
  url          = {http://dx.doi.org/},
  volume       = {63},
  year         = {2003},
}