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Int. J. Mol. Sci. 2017, 18(12), 2711; https://doi.org/10.3390/ijms18122711

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

1
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
2
Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy
*
Author to whom correspondence should be addressed.
Received: 3 November 2017 / Revised: 11 December 2017 / Accepted: 13 December 2017 / Published: 14 December 2017
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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Abstract

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). View Full-Text
Keywords: fibrinogen; afibrinogenemia; hypofibrinogenemia; dysfibrinogenemia; hepatic fibrinogen storage disease; hereditary renal amyloidosis; FGA; FGB; FGG; exome-based epidemiology fibrinogen; afibrinogenemia; hypofibrinogenemia; dysfibrinogenemia; hepatic fibrinogen storage disease; hereditary renal amyloidosis; FGA; FGB; FGG; exome-based epidemiology
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Paraboschi, E.M.; Duga, S.; Asselta, R. Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains. Int. J. Mol. Sci. 2017, 18, 2711.

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