Missense mutations in the human β fibrinogen gene cause congenital afibrinogenemia by impairing fibrinogen secretion
| Autor: | Maria Luisa Tenchini, Sirous Zeinali, Rosanna Asselta, Tatjana Simonic, Stefano Duga, Elena Santagostino, Massimo Malcovati, Pier Mannuccio Mannucci |
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| Rok vydání: | 2000 |
| Předmět: |
medicine.medical_specialty
Mutation Afibrinogenemia Immunology Cell Biology Hematology Hypofibrinogenemia Biology medicine.disease medicine.disease_cause Fibrinogen Biochemistry Congenital afibrinogenemia Endocrinology Internal medicine medicine Missense mutation Platelet Dysfibrinogenemia medicine.drug |
| Zdroj: | Blood. 95:1336-1341 |
| ISSN: | 1528-0020 0006-4971 1336-1341 |
| DOI: | 10.1182/blood.v95.4.1336.004k16_1336_1341 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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