Congenital afibrinogenemia (CAF, OMIM #202400) is a rare autosomal recessive coagulation disorder characterized by hemorrhagic manifestations of variable entity and by severe plasma fibrinogen deficiency. Missense mutations responsible for CAF are rare (10%) and are interestingly clustered in a small subdomain of the protein (the C-terminal globular region of the Bbeta-chain). We here report a novel homozygous missense mutation in the same domain (Bbeta-G434D or “Fibrinogen Mumbai”) identified in an Indian CAF patient, and provide insights into the altered secretory pathway of the mutant protein. Fibrinogen Bbeta-G434D was in vitro expressed and pulse-chase experiments were performed to analyze intracellular and secreted mutant fibrinogen. Endoglycosidase-H sensitivity was used to evaluate translocation from the endoplasmic reticulum to the Golgi. Experimental data showed that Bbeta-G434D impairs fibrinogen secretion probably by altering its translocation to trans-Golgi stacks. Clustering of CAF missense mutations highlights the crucial role of the C-terminal globular region of the Bbeta-chain for the fibrinogen secretion.
Fibrinogen Mumbai: impaired secretion due to a novel missense mutation in the Bbeta-chain gene / L. Monaldini, S. Duga, R. Asselta, M. Malcovati, M.L. Tenchini - In: Abstracts. 7. Convegno Federazione Italiana Scienze della Vita / Federazione Italiana Scienze della Vita. - Riva del Garda : FISV, 2005. - pp. 21 (( Intervento presentato al 7. convegno Convegno Federazione Italiana Scienze della Vita tenutosi a Riva del Garda nel 2005.
Fibrinogen Mumbai: impaired secretion due to a novel missense mutation in the Bbeta-chain gene
L. MonaldiniPrimo
;S. DugaSecondo
;R. Asselta;M. MalcovatiPenultimo
;M.L. TenchiniUltimo
2005
Abstract
Congenital afibrinogenemia (CAF, OMIM #202400) is a rare autosomal recessive coagulation disorder characterized by hemorrhagic manifestations of variable entity and by severe plasma fibrinogen deficiency. Missense mutations responsible for CAF are rare (10%) and are interestingly clustered in a small subdomain of the protein (the C-terminal globular region of the Bbeta-chain). We here report a novel homozygous missense mutation in the same domain (Bbeta-G434D or “Fibrinogen Mumbai”) identified in an Indian CAF patient, and provide insights into the altered secretory pathway of the mutant protein. Fibrinogen Bbeta-G434D was in vitro expressed and pulse-chase experiments were performed to analyze intracellular and secreted mutant fibrinogen. Endoglycosidase-H sensitivity was used to evaluate translocation from the endoplasmic reticulum to the Golgi. Experimental data showed that Bbeta-G434D impairs fibrinogen secretion probably by altering its translocation to trans-Golgi stacks. Clustering of CAF missense mutations highlights the crucial role of the C-terminal globular region of the Bbeta-chain for the fibrinogen secretion.Pubblicazioni consigliate
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