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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 569-576
Identification and characterization of a thrombomodulin gene
mutation coding for an elongated protein with reduced expression in
a kindred with myocardial infarction
Gabriella Kunz,
Helen A. Ireland,
Peter J. Stubbs,
Mel Kahan,
Gary C. Coulton, and
David A. Lane
From the Division of Investigative Science, National Heart and Lung
Institute, Division of Biomedical Sciences, Imperial College School of
Medicine, London and the Matilda and Terence Kennedy Institute of
Rheumatology, London.
Thrombomodulin is an endothelial cell receptor for thrombin. It
functions as a natural anticoagulant by greatly accelerating activation
of protein C by thrombin. Using a direct gene screening strategy we
identified a frameshift insertion mutation, insT 1689, in the
thrombomodulin gene of a patient with myocardial infarction. The
mutation predicts an elongated gene product because of substitution of
the 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis showed that the mutation was also likely to have been present
in a sibling who had had fatal myocardial infarction. Carriers of the
mutant allele express significantly lower amounts of thrombomodulin on
the surface of their monocytes detected by flow cytometry and have
lower levels of soluble thrombomodulin in plasma. Wild type and the
mutant thrombomodulin were expressed in COS-7 cells. Cellular
distribution of the expressed proteins was evaluated by
immunofluorescence microscopy, which showed reduced cell surface
expression and intense juxtanuclear localization of the abnormal
protein. This suggests impaired translocation through the endoplasmic
reticulum/Golgi apparatus. Cells expressing abnormal thrombomodulin had
reduced ability (~2.5-fold) to accelerate the thrombin mediated
activation of protein C. This is the first demonstration of reduced
expression arising from a natural thrombomodulin gene mutation. The
results provide support for the suggestion that gene mutation of
thrombomodulin may be important in the pathogenesis of some cases of
occlusive thrombotic disease.
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