Fibrinogen Bern I: A Hereditary Fibrinogen Variant With Defective Conformational Stabilization by Calcium Ions

Rupp, Christoph; Kuyas, C; Haberli, André; Furlan, Miha; Perret, Beat A.; Beck, Eugene A.

doi:10.1515/9783110865325-018

Cited by 5 publications

(8 citation statements)

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“…In contrast, by SDS-PAGE according to Weber and Osborn -a method which separates a mixture of proteins on the basis of difference in molecular weight -no anomaly in ␥-chain migration was noted, indicating that the abnormal ␥-chain has a normal molecular weight. Similar observations of changes in electrophoretic migration by Laemmli technique have been reported for several other abnormal fibrinogens, all presenting a single substitution in the C-terminal part of the ␥-chain, except fibrinogen Vlissingen which is characterized by deletion of 6 bp (11,(20)(21)(22)(23)(24). They have been ascribed to a change in hydrophobicity or local conformation (25,26).…”

Section: Discussionsupporting

confidence: 77%

“…Furthermore, it should be noted that the amount of the abnormal ␥-chain is less than that of the normal ␥-chain, as determined visually. This phenomenon has already been seen in the fibrinogen Vlissingen ␥-chain (11). This suggests, that the Bastia ␥-chain may be less stable than the normal ␥-chain.…”

Section: Discussionmentioning

confidence: 53%

“…Correction of the defective fibrinogen clotting by calcium has been reported for fibrinogens Bern I (34), Haifa (10), Vlissingen (11) and Osaka V (12). Furthermore, calcium is known to increase the rate of fibrin polymerization (35), but the mechanism by which calcium ions affect the polymerization rate of fibrin is still unresolved.…”

Section: Discussionmentioning

confidence: 99%

“…Often, the defect in these abnormal molecules is located in the C-terminal of the ␥-chain (9). A number of cases have been described that contain a defect that impairs the high affinity binding of Ca 2+ located in the C-terminal part of fibrinogen the ␥-chain (10)(11)(12). This impairment results in a lack of protective effect on plasmin degradation of C-terminal ␥-chain.…”

Section: Introductionmentioning

confidence: 99%

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Fibrinogen Bastia (γ 318 Asp → Tyr) a Novel Abnormal Fibrinogen Characterized by Defective Fibrin Polymerization

Soria²,

Valognes³

et al. 1999

Thromb Haemost

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SummaryA new congenital dysfibrinogen, Fibrinogen Bastia, was discovered in a 20-year-old woman with no clinical symptoms. The plasma thrombin-clotting time was severely prolonged. The functional plasma fibrinogen concentration was low (0.2 mg/ml), whereas the immunological concentration was normal (2.9 mg/ml). Purified fibrinogen Bastia displayed a markedly prolonged thrombin-clotting time related to a delayed thrombin-induced fibrin polymerization. Both the thrombin-clotting time and the fibrin polymerization were partially corrected by the addition of calcium ions. The anomaly of fibrinogen Bastia was found to be located in the γ-chain since by SDS-PAGE performed according to the method of Laemmli two γ-chains were detected, one normal and one with an apparently lower molecular weight. Furthermore, analysis of plasmin degradation products demonstrated that calcium ions only partially protect fibrinogen Bastia γ-chain against plasmin digestion, suggesting that the anomaly is located in the C-terminal part of the γ-chain. Sequence analysis of PCR-amplified genomic DNA fragments of the propositus demonstrated a single base substitution (G → T) in the exon VIII of the γ chain gene, resulting in the amino acid substitution 318 Asp (GAC) → Tyr (TAC). The PCR clones were recloned and 50% of them contained the mutation, indicating that the patient was heterozygous. These data indicate that residue Asp 318 is important for normal fibrin polymerization and the protective effect of calcium ions against plasmin degradation of the C-terminal part of the γ-chain.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fibrinogen Bastia (γ 318 Asp → Tyr) a Novel Abnormal Fibrinogen Characterized by Defective Fibrin Polymerization

Soria²,

Valognes³

et al. 1999

Thromb Haemost

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“…Two-dimensional electrophoresis allows the investigation of dysfibrinogenemias. Thus, we could recently describe an additional y-chain variant in an abnormal fibrinogen variant (Bern I) (28). The technique appears to represent one of the most powerful and promising methods for the resolution of the fibrinogen polypeptide chains.…”

Section: Discussionmentioning

confidence: 99%

Sialic Acid Dependent Polypeptide Chain Heterogeneity of Human Fibrinogen Demonstrated by Two-Dimensional Electrophoresis

Kuyas

Haeberli

1982

Thromb Haemost

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SummaryHuman fibrinogen was compared with asialofibrinogen by two-dimensional electrophoresis to evaluate the contribution of sialic acid to the heterogeneity of the γ- and Bβ-polypeptide chains.Reduced fibrinogen showed three major variants for both the γ- and Bβ-chains. In addition two minor γ-bands with a more acidic isoelectric point than the normal γ-chains were observed. Electrophoresis in the second dimension (SDS) suggests that these most acidic bands are γ-chain-variants with a higher molecular weight. In asialofibrinogen only two predominant variants with more alkaline isoelectric points were present in each chain type.It is concluded that enzymatic removal of sialic acid partially reduces the heterogeneity of the γ- and Bβ-polypeptide chains of human fibrinogen, but additional sources producing charge heterogeneity must be sought.

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Difference in electrophoretic mobility and plasmic digestion profile between four recombinant fibrinogens, γ14;308K, γ308I, γ308A, and wild type (γ308N)

et al. 2000

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We have produced recombinant gamma-chain variant fibrinogens, gamma308K, gamma308I, and gamma308A simultaneously with wild-type fibrinogen, gamma-308N, by genetic protein engineering using Chinese hamster ovary cells. Although all three variant fibrinogens are a result of a single amino acid substitution, the aberrant gamma-chains of gamma308K and gamma308I fibrinogens migrated faster than gamma308N. Furthermore, plasmic digestion profiles were examined in the presence of 5 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or 1 mM CaCl2. In the presence of EGTA, the three variant fibrinogens were digested into D1 and D2 fragments slightly faster than wild type. In addition, the D2 fragment derived from gamma308K was further digested into D3 by plasmin much faster than that from gamma308N. These data suggest that cleavage of gamma356Lys-gamma357Ala bond by plasmin in gamma308K, gamma308I, and gamma308A is slightly accelerated and the gamma302Lys-gamma303Phe bond is cleaved by plasmin rapidly in only the gamma308K variant. Furthermore, the substitution of Lys for gamma308Asn results in the generation of a new plasmin cleavage site between gamma308Lys and gamma309Gly in the presence of EGTA. In conclusion, a substitution at residue gamma308Asn may cause a conformational change in the gammachain of fragment D affecting polymerization and plasmin cleavage.

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Fibrinogen Bern I: A Hereditary Fibrinogen Variant With Defective Conformational Stabilization by Calcium Ions

Cited by 5 publications

References 0 publications

Fibrinogen Bastia (γ 318 Asp → Tyr) a Novel Abnormal Fibrinogen Characterized by Defective Fibrin Polymerization

Fibrinogen Bastia (γ 318 Asp → Tyr) a Novel Abnormal Fibrinogen Characterized by Defective Fibrin Polymerization

Sialic Acid Dependent Polypeptide Chain Heterogeneity of Human Fibrinogen Demonstrated by Two-Dimensional Electrophoresis

Difference in electrophoretic mobility and plasmic digestion profile between four recombinant fibrinogens, γ14;308K, γ308I, γ308A, and wild type (γ308N)

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