Abnormal Fibrinogen Zlín (&amp;#947;Thr21Ile) with Missense Mutation Causing Hypofibrinogenemia

Riedelová-Reicheltová, Zuzana; Riedel, Tomáš; Májek, Pavel; Kotlín, Roman; Geierová, Véra; Suttnar, Jiřı́; Dyr, Jan E.

doi:10.1159/000356781

Cited by 2 publications

(2 citation statements)

References 23 publications

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“…Among them, two mutations that were located in FGG were extremely frequent in the analyzed populations, i.e., p.Ala108Gly and p.Thr47Ile. Both of the mutations have been described in the literature as being causative of hypofibrinogenemia and associated with a mild bleeding tendency [ 25 , 26 , 27 ]. In particular, the p.Ala108Gly variant (also known as Ala82Gly, fibrinogen Dunedin) accounts for the totality of mutated alleles in Ashkenazi Jews, and represents >70% of all mutated alleles among Europeans (for a total of 29 heterozygous individuals among 25,790 Finns, and 456 heterozygous individuals among 126,630 non-Finnish Europeans).…”

Section: Resultsmentioning

confidence: 99%

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

Paraboschi

Duga

Asselta

2017

IJMS

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Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-dysfibrinogenemia, dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1–2 cases per million people. However, the “true” prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 106 in East Asians to 24.5 in 106 in non-Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1–2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG-p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans).

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Section: Resultsmentioning

confidence: 99%

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

Paraboschi

Duga

Asselta

2017

IJMS

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“…Our literature review identified a large number of novel mutations accounting for congenital fibrinogen disorders, both quantitative [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] and qualitative. [65][66][67][68][69][70][71][72][73][74][75][76] The majority of dysfibrinogenemias, inherited as a dominant trait, are caused by heterozygous missense mutations in one of the three fibrinogen genes.…”

Section: Genetic Diagnosis Of Congenital Fibrinogen Disordersmentioning

confidence: 99%

Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders

Neerman-Arbez

Moerloose

Casini

2016

Semin Thromb Hemost

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Congenital fibrinogen disorders are classified into two types of plasma fibrinogen defects: type I (quantitative fibrinogen deficiencies), that is, hypofibrinogenemia or afibrinogenemia, in which there are low or absent plasma fibrinogen antigen levels, respectively, and type II (qualitative fibrinogen deficiencies), that is, dysfibrinogenemia or hypodysfibrinogenemia, in which there are normal or reduced antigen levels associated with disproportionately low functional activity. These disorders are caused by mutations in the three fibrinogen-encoding genes FGA, FGB, and FGG. Afibrinogenemia is associated with mild to severe bleeding, whereas hypofibrinogenemia is often asymptomatic. For these quantitative disorders, the majority of mutations prevent protein production. However, in some cases, missense or late-truncating nonsense mutations allow synthesis of the mutant fibrinogen chain, but intracellular fibrinogen assembly and/or secretion are impaired. Qualitative fibrinogen disorders are associated with bleeding, thrombosis, or both thrombosis and bleeding, but many dysfibrinogenemias are asymptomatic. The majority of cases are caused by heterozygous missense mutations. Here, we review the laboratory and genetic diagnosis of fibrinogen gene anomalies with an updated discussion of causative mutations identified.

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Abnormal Fibrinogen Zlín (γThr21Ile) with Missense Mutation Causing Hypofibrinogenemia

Cited by 2 publications

References 23 publications

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains

Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders

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