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

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