Molecular characterization of the first missense mutation in the fibrinogen Aalpha-chain gene identified in a compound heterozygous afibrinogenemic patient
| Autor: | Rosanna Asselta, Manuela Platé, Flora Peyvandi, Stefano Duga, Maria Luisa Tenchini |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Heterozygote Blotting Western Molecular Sequence Data Aα chain Mutation Missense Biology Compound heterozygosity Fibrinogen medicine.disease_cause Protein ex-vivo expression Frameshift mutation Autosomal recessive trait medicine Animals Humans Missense mutation Amino Acid Sequence Molecular Biology DNA Primers Genetics Mutation Base Sequence Sequence Homology Amino Acid Afibrinogenemia medicine.disease Molecular biology Pedigree Congenital afibrinogenemia Mutagenesis Site-Directed Molecular Medicine Female medicine.drug |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772(7):781-787 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2007.04.005 |
| Popis: | Congenital afibrinogenemia is a rare coagulopathy characterized by extremely low levels of functional and immunoreactive fibrinogen in plasma, associated with a hemorrhagic phenotype of variable severity. It is transmitted as an autosomal recessive trait and is invariantly associated with mutations affecting 1 of the 3 fibrinogen genes (FGA, FGB, and FGG, coding for Aalpha, Bbeta, and gamma chain, respectively). Most genetic defects causing afibrinogenemia are truncating mutations, whereas only few missense mutations (6) have been identified so far, all located in FGB. In this study, the mutational screening of an afibrinogenemic Italian male identified the first missense mutation (Met51Arg) in FGA leading to afibrinogenemia. The patient was a compound heterozygote for a previously described frameshift mutation (1215delT) in the same gene. Met51Arg involves a residue located at the very beginning of the coiled-coil domain, in a region demonstrated to play a pivotal role in hexamer formation. In-vitro expression experiments showed that Met51Arg strongly reduces secretion of hexameric fibrinogen, whereas traces of not completely assembled trimeric intermediate were found in conditioned media. Western blot analysis on the proband's plasma confirmed the presence in vivo of the trimeric fibrinogen, supporting the hypothesis that Met51Arg prevents the final step of fibrinogen assembly. |
| Databáze: | OpenAIRE |
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