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 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.
Nichols
W C
WC
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0650, USA.
Seligsohn
U
U
Zivelin
A
A
Terry
V H
VH
Hertel
C E
CE
Wheatley
M A
MA
Moussalli
M J
MJ
Hauri
H P
HP
Ciavarella
N
N
Kaufman
R J
RJ
Ginsburg
D
D
D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005166:Factor V Deficiency / Q000235:genetics*; D016368:Frameshift Mutation; D008040:Genetic Linkage; D005819:Genetic Markers; D006056:Golgi Apparatus / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis
D017931:DNA Primers; D005819:Genetic Markers; C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins