Fibrinogen Mumbai: impaired secretion due to a novel missense mutation in the Bbeta-chain gene

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.