Molekularbiologie der Gerinnung: Fibrinogen, Faktor XIII

Zusammenfassung

Genetische Defekte des Fibrinogens werden durch ein breites Spektrum an Mutationen in einem der drei beteiligten Strukturgene (FGA, FGB, FGG) verursacht. Sie führen zu einem kompletten oder partiellen Fibrinogenmangel im Plasma (A- bzw. Hypofibrinogenämie) oder zu strukturellen Veränderungen, die das Protein funktionell beeinträchtigen (Dysfibrinogenämien). Während bei den autosomal rezessiv vererbten Afibrinogenämien Nonsense-, Frameshift- und Splice-site-Mutationen im Vordergrund stehen, die zu deutlich verkürzten Polypeptidketten (vor allem Aα) führen, werden die meist heterozygoten Dys- und Hypofibrinogenämien überwiegend durch Missense-Mutationen verursacht, die den Austausch einzelner Aminosäureren zur Folge haben. Bei den quantitativen Fibrinogendefekten wird eine unterschiedlich stark erhöhte Blutungsbereitschaft beobachtet. Die Dysfibrinogenämien treten klinisch sowohl als Blutungs- wie auch als Thromboseneigung in Erscheinung. Einige Defekte sind mit einer Kombination von Blutungs- und thromboembolischen Symptomen assoziiert. Etwa die Hälfte der Fälle von Dysfibrinogenämie sind klinisch asymptomatisch.

Der plasmatische Faktor XIII (FXIII) stellt ein Heterotetramer aus je zwei A- und B-Untereinheiten dar, die von unterschiedlichen Genen kodiert werden. Die häufigste Form des mit Blutungen, Wundheilungsstörungen und einer Neigung zu Spontanaborten einhergehenden genetisch bedingten FXIII-Mangels geht auf Defekte der A-Untereinheit zurück, die wiederum durch ein sehr breites Spektrum von Mutationen verursacht werden. Defekte der B-Untereinheit sind sehr selten und bisher nur in wenigen Fällen molekular aufgeklärt.

Summary

Genetic defects of fibrinogen are caused by a broad spectrum of mutations in one of the three structural genes FGA, FGB and FGG. They result in complete or partial lack of plasma fibrinogen (a- or hypofibrinogenaemia) or in structural abnormalities affecting protein function (dysfibrinogenaemia). In contrast to afibrinogenaemia mainly caused by nonsense, frameshift, and splice site mutations resulting in substantially truncated polypeptide chains (mainly Aα), in hypo- and dysfibrinogenaemias missense mutations lead to the exchange of single amino acids as dominating underlying defect. In the cases with quantitative disorders, bleeding with various degrees of severity is generally observed. Dysfibrinogenaemia is associated with both bleeding or thrombosis or even a combination of haemorrhagic and thromboembolic symptoms. About one half of the dysfibrinogenaemic cases is clinically asymptomatic. The plasmatic factor XIII (FXIII) is a heterotetramer composed of two A and two B subunits encoded by two different genes. FXIII deficiency is associated with bleeding, wound dehiscence and recurrent spontaneous abortions. The most frequent form is caused by defects in the A subunit with a broad spectrum of underlying mutations. Defects of the B subunit are very rare and were molecularly elucidated in only a few cases.

Schlüsselwörter

Fibrinogen - Faktor XIII - Molekulargenetik

Keywords

Fibrinogen - factor XIII - molecular genetics

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