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Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-06-2141.
Submitted July 1, 2003
Accepted July 24, 2003
Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion
Dung Vu, Paula H Bolton-Maggs, Jeremy R Parr, Michael A Morris, and Marguerite Neerman-Arbez*
Division of Medical Genetics, University Medical School and University Hospital, Geneva, Switzerland
Royal Liverpool Children's Hospital, Liverpool, United Kingdom
Department of Pediatrics, Stoke Mandeville Hospital, Aylesbury, United Kingdom
Division of Medical Genetics, University Medical School and University Hospital, Geneva, Switzerland; Division of Angiology and Hemostasis, University Hospital, Geneva, Switzerland
* Corresponding author; email: Marguerite.Arbez{at}medecine.unige.ch.
Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen alpha chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for two mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Co-expression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant beta-chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation.
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