Hypofibrinogenemia Associated with a Heterozygous C→T Nucleotide Substitution at Position −1138 BP of the 5′‐Flanking Region of the Fibrinogen Aα‐Chain Gene

Okumura, Nobuo; Terasawa, Fumiko; Yonekawa, Osamu; Hamada, Etsuko; Kaneko, Hiroshi

doi:10.1111/j.1749-6632.2001.tb03539.x

Cited by 8 publications

(6 citation statements)

References 7 publications

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“…This was a heterozygous variant À1138C4T upstream of FGA identified in heterozygosity in a Japanese patient with hypofibrinogenemia [Okumura et al, 2001]. Functional analysis using a luciferase reporter gene downstream of the normal (À1138C) and mutant (À1138T) sequence suggested that the À1138T allele had significantly reduced enhancer activity (only 25% of the activity measured for the À1138C allele in HepG2 cells).…”

Section: Promoter Mutationsmentioning

confidence: 99%

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Neerman-Arbez

Moerloose

2007

Hum. Mutat.

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Communicated by Arupa GangulyFibrinogen is synthesized in hepatocytes in the form of a hexamer composed of two sets of three polypeptides (Aa, Bb, and c). Each polypeptide is encoded by a distinct gene, FGA, FGB, and FGG, all three clustered in a region of 50 kb on 4q31. Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Although the disease was first described in 1920, the genetic defect responsible for this disorder long remained unknown. We identified the gene and the first causative mutations for this disease in a nonconsanguineous Swiss family in 1999. Since this first report, 61 additional mutations, the majority in FGA, have been identified in patients with afibrinogenemia (in homozygosity or in compound heterozygosity) or in heterozygosity in hypofibrinogenemia, since many of these patients are in fact asymptomatic carriers of afibrinogenemia mutations. Mutations in the fibrinogen genes may lead to deficiency of fibrinogen by several mechanisms: these can act at the DNA level, at the RNA level by affecting mRNA splicing or stability, or at the protein level by affecting protein synthesis, assembly, or secretion. The expression of selected mutations has shown that mechanisms acting at all three levels play a role in the molecular basis of this disease. We report here the identification of 10 novel mutations, of which eight are localized in FGA, thus increasing the total number of causative mutations identified to 72 and confirming the relative importance of FGA in the molecular basis of fibrinogen deficiency. Hum Mutat 28(6), [540][541][542][543][544][545][546][547][548][549][550][551][552][553] 2007. r r 2007 Wiley-Liss, Inc.

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Section: Promoter Mutationsmentioning

confidence: 99%

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Neerman-Arbez

Moerloose

2007

Hum. Mutat.

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“…This seems to confirm that the Aa chain synthesis is not rate-limiting and that one normal allele is sufficient for achieving normal synthesis. Heterozygosity has been found only for the )1138c>t mutation affecting a regulatory sequence and reducing transcription [9]. The Aa Grand Lyon mutation is also present on a sole allele.…”

mentioning

confidence: 99%

LETTERS TO THE EDITOR: Four cases of hypofibrinogenemia associated with four novel mutations

Hanss

Ffrench

Vinciguerra

et al. 2005

Journal of Thrombosis and Haemostasis

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“…However, this heterozygous mutation would not necessarily cause hypofibrinogenaemia even if it were to affect both alleles (i. e. trans acting). In fact, the authors who reported this mutation do not exclude the possibility that the affected individual might have a large heterozygous deletion in one of the fibrinogen genes [69].…”

Section: Discussionmentioning

confidence: 95%

“…This suggests that any aberrant Aa chains produced would be outcompeted by the surplus of normal chains, resulting in low or no expression of these variants in the circulating fibrinogen of heterozygotes. In fibrinogen Hamamatsu, which is associated with hypofibrinogenaemia, the mutant -1138 T allele was shown to decrease a gene transcription by 35 % compared with the wild-type -1138 C allele [69]. However, this heterozygous mutation would not necessarily cause hypofibrinogenaemia even if it were to affect both alleles (i. e. trans acting).…”

Section: Discussionmentioning

confidence: 97%

The molecular mechanisms of congenital hypofibrinogenaemia

Maghzal

Brennan

Homer

et al. 2004

CMLS, Cell. Mol. Life Sci.

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Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes (alpha, beta and gamma). However, it does not usually result in a clinically significant condition unless inherited in a homozygous or compound heterozygous state, where it results in a severe bleeding disorder, afibrinogenaemia. Various protein and expression studies have improved our understanding of how mutations causing hypo- and afibrinogenaemia affect secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations can perturb chain assembly as in the gamma153 Cys-->Arg case, while others such as the Bbeta Leu-->Arg and the Bbeta414 Gly-->Ser mutations allow intracellular hexamer assembly but inhibit protein secretion. An interesting group of mutations, such as gamma284 Gly-->Arg and gamma375 Arg-->Trp, not only cause hypofibrinogenaemia but are also associated with liver disease. The nonexpression of these variant chains in plasma fibrinogen is due to retention in the endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.

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Hypofibrinogenemia Associated with a Heterozygous C→T Nucleotide Substitution at Position −1138 BP of the 5′‐Flanking Region of the Fibrinogen Aα‐Chain Gene

Cited by 8 publications

References 7 publications

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations

LETTERS TO THE EDITOR: Four cases of hypofibrinogenemia associated with four novel mutations

The molecular mechanisms of congenital hypofibrinogenaemia

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