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At least 19 recordsLinked to original sources
PubMed2003

Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen alpha-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant beta chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation.

Adult↗
PubMed2000

Missense mutations in the human beta fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. Although several mutations in the fibrinogen genes associated with dysfibrinogenemia and hypofibrinogenemia have been described, the genetic defects of congenital afibrinogenemia are largely unknown, except for a recently reported 11-kb deletion of the fibrinogen Aalpha-chain gene. Nevertheless, mutation mechanisms other than the deletion of a fibrinogen gene are likely to exist because patients with afibrinogenemia showing no gross alteration within the fibrinogen cluster have been reported. We tested this hypothesis by studying the affected members of two families, one Italian and one Iranian, who had no evidence of large deletions in the fibrinogen genes. Sequencing of the fibrinogen genes in the 2 probands detected 2 different homozygous missense mutations in exons 7 and 8 of the Bbeta-chain gene, leading to amino acid substitutions Leu353Arg and Gly400Asp, respectively. Transient transfection experiments with plasmids expressing wild-type and mutant fibrinogens demonstrated that the presence of either mutation was sufficient to abolish fibrinogen secretion. These findings demonstrated that missense mutations in the Bbeta fibrinogen gene could cause congenital afibrinogenemia by impairing fibrinogen secretion. (Blood. 2000;95:1336-1341)

Adolescent↗
PubMed2000

Afibrinogenemia: first identification of a splicing mutation in the fibrinogen gamma chain gene leading to a major gamma chain truncation.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of plasma fibrinogen and by a bleeding tendency ranging from mild to moderately severe. Beside a deletion of the almost entire Aalpha-chain gene, only 2 missense mutations in the C-terminal domain of the Bbeta-chain have been very recently described as being associated with afibrinogenemia. We studied a Pakistani patient with unmeasurable plasma levels of functional and immunoreactive fibrinogen. Sequencing of the fibrinogen genes revealed a homozygous G-->A transition at position +5 of intron 1 of the gamma-chain gene. The predicted mutant fibrinogen gamma-chain would contain the signal peptide, followed by a short stretch of aberrant amino acids, preceding a premature stop codon. To demonstrate the causal role of the identified mutation, we prepared expression vectors containing a region of the fibrinogen gamma-chain gene spanning from exon 1 to intron 4 and carrying either a G or an A at position +5 of intron 1. Transient transfection of the mutated plasmid in HeLa cells, followed by RNA extraction and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, allowed us to demonstrate the production of an erroneously spliced messenger RNA (mRNA), retaining intron 1, as shown by direct sequencing. A normal splicing occurred in HeLa cells transfected with the wild-type plasmid. This is the first report of a mutation in the fibrinogen gamma-chain gene causing afibrinogenemia and indicates that, in addition to the Aalpha and Bbeta-chain genes, the gamma-chain gene must also be considered in mutation screening for afibrinogenemia.

Afibrinogenemia↗
PubMed1994

Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution.

We describe a patient with congenital afibrinogenemia who showed elevated prothrombin activation fragments (F1 + 2) indicating increased thrombin formation. This finding was unexpected since it has hitherto been thought that patients with congenital hypo- or afibrinogenemia have no evidence of increased utilization or accelerated consumption of coagulation factors. No other possible reasons for the elevation of F 1 + 2 were found. Upon fibrinogen substitution F1 + 2 decreased and were again increasing when fibrinogen concentration in plasma fell to very low levels. These findings raise the question of whether increased thrombin formation should be understood as a compensatory mechanism in congenital afibrinogenemia.

Adolescent↗
PubMed2001

Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes.

Congenital afibrinogenemia is an autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease in a non-consanguineous Swiss family. These were homozygous deletions of approximately 11 kb of the fibrinogen alpha chain gene (FGA). Our subsequent study revealed that the majority of cases were attributable to truncating mutations in FGA, with the most common mutation affecting the donor splice site in FGA intron 4 (IVS4+1 G-->T). Here, we report 13 further unrelated patients with mutations in FGA, confirming the relative importance of this gene compared with FGG and FGB in the molecular aetiology of afibrinogenemia. Three other patients were homozygous for mutations in FGG. Eight novel mutations were identified: five in FGA and three in FGG. Sufficient mutation data is now available to permit an effective strategy for the genetic diagnosis of congenital afibrinogenemia.

Afibrinogenemia↗
PubMed1996

Bilateral vertebral artery dissection in a patient with afibrinogenemia.

BACKGROUND: Afibrinogenemia, a rare coagulation disorder, has not been associated with vertebral artery dissections. CASE DESCRIPTION: A 28-year-old woman with afibrinogenemia developed spontaneous neck pain followed by a right medullary infarction, and MR angiography showed extensive bilateral vertebral artery dissection. She was treated with fibrinogen replacement and anticoagulants and showed a favorable evolution, with only mild residual right upper arm incoordination. CONCLUSIONS: In this patient spontaneous bilateral vertebral artery dissection complicated afibrinogenemia. Since anticoagulant therapy is usually indicated for arterial dissection, this association created a therapeutic problem. This patient received anticoagulants with fibrinogen replacement, which resulted in a favorable evolution.

Adult↗
PubMed1993

Association of congenital afibrinogenemia and K-dependent protein C deficiency--a case report.

The authors describe a rare case of congenital afibrinogenemia with concomitant K-dependent protein C deficit that was brought to our observation for ischemic lesions of the foot in association with fibrinogen concentrate infusions. These lesions can be attributed to the association of various factors: fibrinogen infusion without heparin coverage, microtrauma, and protein C (PC) deficit. In fact, thromboembolic complications during afibrinogenemia were previously reported usually in association with substitutive therapy, and it is also known that PC deficit predisposes to thrombotic complications. The the authors' knowledge, the case described by them is the first in which PC deficit is associated with afibrinogenemia. This association cannot be explained by a common genetic mechanism because the genes for fibrinogen and for protein C are located on different chromosomes (chromosomes 4 and 2 respectively).

Adolescent↗
PubMed2002

Outcome of donor splice site mutations accounting for congenital afibrinogenemia reflects order of intron removal in the fibrinogen alpha gene (FGA).

Congenital afibrinogenemia (Mendelian Inheritance in Man #202400) is a rare, autosomal recessive disorder characterized by the complete absence of circulating fibrinogen. Our recent studies on the molecular basis of the disease showed that the most common genetic defect is a donor splice mutation in fibrinogen alpha gene (FGA) intron 4, IVS4+1G>T. Two other FGA donor splice mutations, in intron 1 (IVS1+3A>G) and intron 3 (IVS3+1_+4delGTAA), were identified in afibrinogenemia patients. Because it was impossible to directly study the effect of these mutations on mRNA splicing in patient hepatocytes, we used a transfected cell approach, which previously allowed us to show that the common IVS4 mutation causes afibrinogenemia due to the activation of multiple cryptic donor splice sites. In this study, analysis of the IVS3delGTAA mutation showed exon 3 skipping in 99% of transcripts and exons 2 and 3 skipping in 1% of transcripts. The different outcomes of these donor splice mutations appear to follow the model proposed in a study of fibrillar collagen genes, where donor splice mutations occurring in a rapidly spliced intron with respect to upstream introns lead in most cases to exon skipping, while mutations in later-spliced introns lead to intron inclusion or cryptic splice-site utilization. Indeed, we found that in FGA intron 3 was preferentially spliced first, followed by intron 2, intron 4, and intron 1.

Afibrinogenemia↗
PubMed2002

Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites.

Congenital afibrinogenemia is a rare inherited coagulopathy, characterized by very low or unmeasurable plasma levels of immunoreactive fibrinogen. So far, 25 mutations have been identified in afibrinogenemia, 17 in the Aalpha, 6 in the gamma, and only 2 in the Bbeta fibrinogen-chain genes. Here, 2 afibrinogenemic probands, showing undetectable levels of functional fibrinogen, were screened for causative mutations at the genomic level. Sequence analysis of the 3 fibrinogen genes disclosed 2 novel homozygous mutations in introns 6 and 7 of the Bbeta-chain gene (IVS6 + 13C > T and IVS7 + 1G > T), representing the first Bbeta-chain gene splicing mutations described in afibrinogenemia. The IVS6 + 13C > T mutation predicts the creation of a donor splice site in intron 6, whereas the IVS7 + 1G > T mutation causes the disappearance of the invariant GT dinucleotide of intron 7 donor splice site. To analyze the effect of these mutations, expression plasmids containing Bbeta-chain minigene constructs, either wild-type or mutant, were transfected in HeLa cells. Assessed by semiquantitative analysis of reverse transcriptase-polymerase chain reaction products, the IVS7 + 1G > T mutation resulted in multiple aberrant splicings, while the IVS6 + 13C > T mutation resulted in activation of a new splice site 11 nucleotides downstream of the physiologic one. Both mutations are predicted to determine protein truncations, supporting the importance of the C-terminal domain of the Bbeta chain for fibrinogen assembly and secretion.

Adolescent↗
PubMed2003

Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family.

Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease, homozygous deletions of approximately 11 kb of the fibrinogen alpha chain gene (FGA). Subsequent analyses revealed that most afibrinogenemia alleles are truncating mutations of FGA, although mutations in all 3 fibrinogen genes, FGG, FGA and FGB have been identified. In this study, we performed the first prenatal diagnosis for afibrinogenemia. The causative mutation in a Palestinian family was a novel nonsense mutation in the FGB gene, Trp467Stop (W467X). Expression of the Trp467Stop mutant FGB cDNA in combination with wild-type FGA and FGG cDNAs showed that fibrinogen molecules containing the mutant beta chain are not secreted into the media. The fetus was found to be heterozygous for the Trp467Stop mutation by direct sequencing and by linkage analysis, a result that was confirmed in the newborn by intermediate fibrinogen levels.

Abortion, Spontaneous↗
PubMed2001

Activation of multiple cryptic donor splice sites by the common congenital afibrinogenemia mutation, FGA IVS4 + 1 G-->T.

Our recent studies on the molecular basis of the autosomal recessive disorder congenital afibrinogenemia showed that the most common mutation is a donor splice mutation in FGA intron 4, IVS4 + 1 G-->T, accounting for approximately half of disease alleles. The effect of this mutation on messenger RNA (mRNA) splicing, however, remained unproven. COS-7 cells transfected with a normal plasmid construct produced 100% mRNA molecules with correct splicing, whereas cells transfected with a mutant construct produced multiple aberrant mRNAs, due to utilization of cryptic donor splice sites situated in exon 4 and intron 4. One particular site situated 4 base pairs (bp) downstream of the normal site was used in 85% of transcripts causing afibrinogenemia by a 4-bp insertion-frameshift, leading to premature alpha-chain truncation. Our results confirm the utility of transfecting COS-7 cells to study mRNA splice-site mutations and demonstrate that the common FGA IVS4 variant is a null mutation leading to afibrinogenemia.

Afibrinogenemia↗
PubMed2000

Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.

Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.

Adolescent↗
PubMed2002

Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenemia.

BACKGROUND AND OBJECTIVES: Congenital afibrinogenemia is a rare coagulation disorder whose molecular basis is still poorly characterized. Most mutations have been identified in the fibrinogen Aalpha- and gamma-chain genes, whereas only two missense mutations have been reported in the Bbeta-chain gene. The aim of this work was to widen knowledge about the mutational spectrum of this disease by analyzing the molecular bases of congenital afibrinogenemia in three unrelated Iranian patients. DESIGN AND METHODS: All patients showed unmeasurable levels of clottable fibrinogen in plasma. Mutational screening was performed by sequencing the whole coding region, including exon-intron boundaries and part of the promoter region of the three fibrinogen genes. RESULTS: Sequencing in one patient revealed the presence of a novel nonsense mutation (3282C-->T) in exon 2 of the fibrinogen Bbeta-chain gene, causing a severe truncation of the corresponding polypeptide (R17X). In the remaining probands, two already known small deletions (4209delA and 4220delT), both located in exon 5 of the fibrinogen Aalpha-chain gene, were identified, and their effect at the protein level explored by computer-assisted analysis. INTERPRETATION AND CONCLUSIONS: The identification of the first truncating mutation in the fibrinogen Bbeta-chain gene confirms the involvement of all three fibrinogen genes in the pathogenesis of congenital afibrinogenemia and widens the mutational spectrum of the disease. This knowledge is clinically essential in order to carry out prenatal diagnosis in families at risk.

Adolescent↗
PubMed1992

Coexistence of congenital afibrinogenemia and protein C deficiency in a patient.

A rare association of congenital afibrinogenemia and hereditary protein C deficiency is described in a 37-year-old female who suffered from ischemic necrosis in the left first toe. The diagnosis of afibrinogenemia was assessed by the absence of fibrinogen in clotting and immunological assays. The diagnosis of hereditary heterozygous type I protein C deficiency was based on the evidence of proportional decreases of activity and antigen of plasma protein C in the propositus, her mother, and two maternal aunts.

Adult↗
PubMed1981

Demonstration of a double hereditary pattern for congenital afibrinogenemia.

Six patients with congenital afibrinogenemia belonging to four kindreds were studied with regard to hereditary pattern. In two families the hereditary pattern appeared to be autosomal recessive; in the two other pedigrees, on the contrary, the pattern seems autosomal intermediate. In the first type, all family members, excluding the patients, showed normal fibrinogen levels; in the second type, family members could be divided into two groups: normal and heterozygotes. The heterozygotes had fibrinogen levels of 192 +/- 30 mg/dl, definitely lower than that of a normal control population. The average level of the normal relatives was 361 +/- 81.9 mg/dl, practically identical to that of a normal control group unrelated to the homozygotes. In the past these differences were thought to be secondary to variances in fibrinogen assays from one laboratory to the other. It now appears that they are real ones since they can be observed in the same laboratory using the same fibrinogen technique. It must be concluded that congenital afibrinogenemia shows two patterns of hereditary transmission, one autosomal recessive and the other autosomal intermediate.

Adolescent↗
PubMed1975

Platelet adhesiveness and aggregation in congenital afibrinogenemia. An investigation of three patients with post-transfusion, cross-correction studies between two of them.

Platelet adhesiveness and aggregation were studied in three patients with congenital afibrinogenemia. The results obtained may be summarized as follows: The retention of platelets to a glass-bead filter determined with the Salzman method was significantly decreased; it was normal after fibrinogen infusion. With a modification of the Hellem test the values obtained were slightly decreased. Adrenalin-induced aggregation was absent whereas ADP-and collagen-induced aggregation was near normal or slightly decreased. Thrombofax aggregation was absent in citrated plasma. The abnormalities of platelet aggregation were corrected after fibrinogen infusion or after addition in vitro of fibrinogen, hemofilia A plasma and PPP obtained from an afibrinogenemic patient after fibrinogen infusion. The abnormalities of platelet aggregation were corrected well by ADP, collagen and Thrombofax in heparinized blood, but only a slight correction of adrenalin-induced aggregation was noted. Thrombin aggregation proved to be normal with the higher concentrations, whereas it was defective with the lower ones. Ristocetin aggregation was normal in citrated plasma at the concentration of 1.5 mg per ml but it was absent at the lower concentration (1.0 mg per ml). Ristocetin aggregation was, on the other hand absent in heparinized blood regardless of the concentration. These findings are in agreement with the presence of a prolonged bleeding time in congenital afibrinogenemia and suggest that fibrinogen plays an important role in platelet aggregation and adhesiveness.

Adenosine Diphosphate↗
PubMed2002

Unusually quick resorption of an intracerebral hemorrhage in congenital afibrinogenemia.

Neuroimaging diagnostics of cerebral hemorrhage in congenitally afibrinogenic patients may be compromised by different pitfalls. We describe the case of a 28-year-old patient with the diagnosis of congenital afibrinogenemia who suffered a large intracerebral hemorrhage. Initial cerebral computed tomography showed typical bleeding, but follow-up cerebral CT scans 1 and 2 weeks later revealed an unusually quick and subtotal resorption of hemorrhage with only a small hypodense lesion within the former bleeding area left. Imaging findings and differential diagnosis are discussed with respect to previous reports about intracerebral hemorrhage in afibrinogenemia.

Adult↗