Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains
AbstractFibrinogen 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
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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.
Paraboschi EM, Duga S, Asselta R. Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains. International Journal of Molecular Sciences. 2017; 18(12):2711.Chicago/Turabian Style
Paraboschi, Elvezia M.; Duga, Stefano; Asselta, Rosanna. 2017. "Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains." Int. J. Mol. Sci. 18, no. 12: 2711.
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