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A Thr359Met mutation in factor VII of a patient with a hereditary
deficiency causes defective secretion of the molecule
AA Arbini, M Mannucci and KA Bauer
Hematology-Oncology Section, Department of Medicine, Brockton-West Roxbury
Department of Veterans Affairs Medical Center.
We elucidated the genetic basis responsible for factor VII deficiency in an
Italian woman with a severe bleeding diathesis. In the allele inherited
from the patient's father, we identified a G to A mutation at nucleotide
6070 at the 5' splice site of intron 4 and a G to A substitution at
nucleotide 10976 resulting in the Arg353Gln polymorphism. The maternal
allele demonstrated a C to T substitution at nucleotide 10994 resulting in
Thr359Met. The mutation at nucleotide 6070 alters an invariant GT
dinucleotide and disrupts normal mRNA processing. To investigate the
mechanism by which Thr359Met reduces factor VIl levels, we expressed wild
type factor VII cDNA (FVIIwt) and a mutant factor VII cDNA containing the
base substitution resulting in Met359 (FVII359M) in Chinese hamster ovary
cells (CHO). In cells transfected with the mutant factor VII cDNA, FVII359M
accumulated intracellularly, and no factor VII was detected in the media
after 3 hours of chase. The carbohydrate side chains associated with
FVII359M were sensitive to Endo H digestion, which indicates that the
protein is retained in the endoplasmic reticulum. Analysis of cell lysates
also showed that FVII359M was associated with the 78 kD protein
corresponding to GRP78/BiP. We conclude that a Thr359Met mutation in factor
VII results in a severe secretion defect that probably results from
abnormal folding of the molecule.
Volume 87,
Issue 12,
pp. 5085-5094,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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