Linked Life Data

12595305

Source:http://linkedlifedata.com/resource/pubmed/id/12595305

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2003-7-18
pubmed:abstractText
There is increasing evidence that serpin conformational alteration caused by single point mutations can be responsible for protein deficiency associated with human diseases. A typical example is the alpha1-antitrypsin deficiency caused by the Z variant carrying a Glu342Lys substitution. Only a few cases of "conformational disease" involving other serpins have been described so far. We investigated a severe antithrombin deficiency in a 13-month-old child with fever and cerebral venous thrombosis. The infant was found to be homozygous for a new antithrombin gene mutation (7396T>C, predicting a Phe229Leu antithrombin variant), and heterozygous for the factor V Leiden mutation. Mild atypical antithrombin deficiency was found in both parents, who were first cousins, asymptomatic, and heterozygous for the same antithrombin gene mutation. The Phe229Leu variant, which does not readily fit into the current classification of antithrombin deficiency, was shown to be a thermolabile antithrombin that spontaneously polymerized in the proband's circulation. This points to a key role for the conserved Phe at position 229, which is near the reactive site loop in a region critical for serpin function and stability. Molecular modeling suggested how the mutation might destabilize this region of the protein and thereby favor reactive site loop insertion and polymerization. This study provides the first direct evidence of antithrombin polymerization in vivo causing antithrombin deficiency and severe thrombotic disease.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0006-4971
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
102
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
919-25
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Antithrombin Phe229Leu: a new homozygous variant leading to spontaneous antithrombin polymerization in vivo associated with severe childhood thrombosis.
pubmed:affiliation
Service d'Hématologie Biologique A, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France. veronique.picard@cep.u-psud.fr
pubmed:publicationType
Journal Article, Case Reports