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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4247-4248. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mosesson, M. W. Search for Related Content PubMed Articles by Mosesson, M. W. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Afibrinogenemia in a compound heterozygote: making sense out of missense Congenital afibrinogenemia is an autosomal recessive disorder characterized by the absence of fibrinogen from the circulation. It had long been anticipated that the basis for this disorder would be rooted in a homozygous defect in one or another of the fibrinogen , , and genes: FGA, FGB, and FGG. Indeed, the first reported genetic analysis of an afibrinogenemic subject by Neerman-Arbez et al1 showed a homozygous 11-kb deletion in FGA. Since then, numerous homozygous fibrinogen gene mutations involving each of the genes have been described, and all but a few are null mutations (frameshift, nonsense, or splice-site). However, the report in this issue by Vu and colleagues (page 4413) shows that afibrinogenemia also occurred in a subject displaying compound heterozygosity of FGB. Their descriptive analysis has provided new insights into the pathogenesis of this disorder. There are 6 fibrinogen gene mutations in afibrinogenemic or hypofibrinogenemic subjects that involve missense mutations of FGB, and they occur in a segment of the gene that corresponds to the C-terminal portion of the fibrinogen B chain. Parenthetically, this region is highly conserved among vertebrates. In 2 cases of afibrinogenemia, expression of the defective gene coupled with studies of intracellular or secreted hexameric fibrinogen showed that assembly to hexamers occurred but that secretion was deficient.2 In a heterozygote manifesting hypofibrinogenemia, a mutation in the FBG region resulted in truncation at B440.3 In another such family, an FGB mutation 3 codons upstream (W467X) also resulted in B chain truncation and nonsecretion.4 In the present report by Vu et al, an afibrinogenemic subject was found to have compound heterozygous mutations of FGB. Each of the heterozygous parents was hypofibrinogenemic. One of the FGB mutations was a previously described nonsense mutation in the N-terminal coding region that led to severe B chain truncation.5 The second FGB mutation involved a missense mutation in the C-terminal coding region leading to a G444S substitution. Coexpression of the G444S mutant plus wild-type B chains in combination with normal FGA and FGG showed that an assembled fibrinogen hexamer was still secreted. In contrast, coexpression of normal fibrinogen with the mutant G444S FGB alone eliminated secretion, thereby providing a coherent explanation for afibrinogenemia in the compound heterozygotic state. As a finale to this discussion of missense, a recently reported heterozygous FGB mutation, R285H, resulted in hypofibrinogenemia.6 As emphasized by Vu et al, such mutations in the C-terminal coding region of FGB confirm the importance of an intact C-terminal B chain for successful fibrinogen secretion. Michael W. Mosesson The Blood Center of Southeastern Wisconsin References Neerman-Arbez M, Honsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen [correction of fibrogen] alpha-chain gene (FGA) causes congenital afibrogenemia. J Clin Invest. 1999;103: 215-218.[Medline] [Order article via Infotrieve] Duga S, Asselta R, Santagostino E, et al. Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion. Blood. 2000;95: 1336-1341.[Abstract/Free Full Text] Homer VM, Brennan SO, Ockelford P, George PM. Novel fibrinogen truncation with deletion of Bbeta chain residues 440-461 causes hypofibrinogenaemia. Thromb Haemost. 2002;88: 427-431.[Medline] [Order article via Infotrieve] Neerman-Arbez M, Vu D, Abu-Libdeh B, Bouchardy I, Morris MA. Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood. 2003;101: 3492-3494.[Abstract/Free Full Text] Asselta R, Spena S, Duga S, et al. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenemia. Haematologica. 2002;87: 855-859.[Abstract/Free Full Text] Maghzal GJ, Brennan SO, Fellowes AP, Spearing R, George PM. Familial hypofibrinogenaemia associated with heterozygous substitution of a conserved arginine residue; Bbeta255 ArgHis (Fibrinogen Merivale). Biochim Biophys Acta. 2003;1645: 146-151.[Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mosesson, M. W. Search for Related Content PubMed Articles by Mosesson, M. W. Social Bookmarking                   What's this?

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