Fibrinogen Mannheim II: a novel γ307 His→Tyr substitution in the γD domain causes hypofibrinogenemia

Abstract

Summary. Background: In recent years it has become clear that the molecular investigation of hypofibrinogenemia provides unique insight into regions of the fibrinogen molecule that are important in molecular assembly, secretion and stability. Objectives: To investigate a case of hypofibrinogenemia at the molecular level. Patients and methods: The study was conducted on a 37-year-old woman from Mannheim, Germany, who had an antigenic plasma fibrinogen concentration of 0.86 g L )1. Mutation screening was performed by DNA sequencing and the effect of the identified mutation was investigated at the protein level. Results: Analysis of exon 8 of the fibrinogen c gene identified a heterozygous CAT fi TAT transition at codon 307. This novel His fi Tyr substitution was not detected when plasma fibrinogen was analyzed by electrospray ionization mass spectrometry. The mutation predicts a mass increase of 26 Da in the c chain, but purified c chains had a normal mass, indicating non-expression of the c Tyr307 chain in plasma fibrinogen. Conclusions: This work reports a novel c307 His fi Tyr mutation (fibrinogen Mannheim II) that causes hypofibrinogenemia. Crystal structures show that His307 is located immediately adjacent to three residues that have been implicated in fibrin polymerization at the D:D interface. However, the histidine residue appears critical in maintaining structure of the fibrinogen cD domain, rather than in determining function.

Identification and characterization of novel mutations implicated in congenital fibrinogen disorders

“…Other fibrinogen mutations have been reported in this part of the D region and have been associated with bleeding and thrombosis. 37,38 There are several limitations to this study. For example, the rigidity and flexibility assessments derived from molecular modeling experiments in this study reflect the properties of fibrinogen in the static state and there could be differences when extrapolating the static function and applying it to the dynamic environment.…”

“…However, individuals with this mutation in our cohort presented with both bleeding and thrombosis, indicating the limitations of this approach. Other fibrinogen mutations have been reported in this part of the D region and have been associated with bleeding and thrombosis 37, 38…”

The rules of variation: Amino acid exchange according to the rotating circular genetic code

“…Examples of some non-conservative changes that break the rules of variation and may end with diseases are Gly–Arg (Armstrong et al, 1996), Pro–Leu and Ala–Glu (Shin et al, 2000), Gly–Asp, causing cystic fibrosis (Hamosh et al, 1992), Gly–Val (Chiu et al, 1993), Glu–Val, causing sickle cell anemia (Serjeant and Serjeant, 1972), Val–Phe (Stafforini et al, 1996), Arg–Gln (Larsen et al, 1998), Glu–Ala (Sluyter et al, 2004), Ser–Cys (Chen et al, 2001), Ser–Pro (Chen et al, 1992), Arg–Pro (Sheppard et al, 1993), Pro–His (Humphries et al, 1990), His–Pro (Dalla-Venezia et al, 1993), His–Tyr (Dear et al, 2004), Tyr–Ala (Lucio and Mazzoni, 2008), Leu–Pro (Belsham et al, 1995), Val–Cys (Saito et al, 2000), and Phe–Cys (Mundo et al, 2001). …”

A novel fibrinogen variant – Praha I: hypofibrinogenemia associated with γ Gly351Ser substitution

“…Hypofibrinogenemias, represented with normal thrombin times and normal fibrinopeptide release, coupled with point mutations in the FGG gene, were found in fibrinogen Dorfen (6) ( γ 289 Ala→Val), fibrinogen Muncie (5) ( γ 371 Thr→Ile) and fibrinogen Mannheim II (17) ( γ 307 His→Tyr). These heterozygous mutations probably destabilize the fibrinogen molecule and the resulting abnormal fibrinogens are either not expressed in plasma or their plasma half‐life is extremely short.…”