Mutations in the ER–Golgi Intermediate Compartment Protein ERGIC-53 Cause Combined Deficiency of Coagulation Factors V and VIII

Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER–Golgi intermediate compartment, was mapped to a YAC and BAC contig...

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Bibliographic Details
Published in:Cell 1998-04, Vol.93 (1), p.61-70
Main Authors: Nichols, William C, Seligsohn, Uri, Zivelin, Ariella, Terry, Valeri H, Hertel, Colette E, Wheatley, Matthew A, Moussalli, Micheline J, Hauri, Hans-Peter, Ciavarella, Nicola, Kaufman, Randal J, Ginsburg, David
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Base Sequence
Chromosome Mapping
Chromosomes, Human, Pair 18
DNA Primers
Endoplasmic Reticulum - metabolism
Factor V Deficiency - genetics
Frameshift Mutation
Genetic Linkage
Genetic Markers
Golgi Apparatus - metabolism
Hemophilia A - genetics
Homozygote
Humans
Mannose-Binding Lectins
Membrane Proteins - biosynthesis
Membrane Proteins - genetics
Point Mutation
Polymerase Chain Reaction
Polymorphism, Genetic
Protein Biosynthesis
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Summary:Combined deficiency of factors V and VIII is an autosomal recessive bleeding disorder resulting from alterations in an unknown gene on chromosome 18q, distinct from the factor V and factor VIII genes. ERGIC-53, a component of the ER–Golgi intermediate compartment, was mapped to a YAC and BAC contig containing the critical region for the combined factors V and VIII deficiency gene. DNA sequence analysis identified two different mutations, accounting for all affected individuals in nine families studied. Immunofluorescence and Western analysis of immortalized lymphocytes from patients homozygous for either of the two mutations demonstrate complete lack of expression of the mutated gene in these cells. These findings suggest that ERGIC-53 may function as a molecular chaperone for the transport from ER to Golgi of a specific subset of secreted proteins, including coagulation factors V and VIII.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81146-0