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Molecular and cellular basis for type I heparin cofactor II deficiency
(heparin cofactor II Awaji)
S Kondo, F Tokunaga, K Kario, T Matsuo and T Koide
Department of Life Science, Faculty of Science, Himeji Institute of
Technology, Harima Science Park City, Hyogo, Japan.
Heparin cofactor II (HCII) is a serine proteinase inhibitor in human plasma
that rapidly inhibits thrombin in the presence of dermatan sulfate or
heparin. To understand the molecular mechanism for HCII deficiency in a
patient with reduced circulating HCII antigen, we studied a Japanese
patient with type I HCII deficiency who suffered from angina pectoris and
coronary artery disease. Polymerase chain reaction (PCR)-based sequence
analysis showed that the propositus' gene for HCII (HCII Awaji gene) had a
thymine insertion after codon (GAT) for Asp88 in exon II, resulting in a
frameshift mutation. Consequently, the abnormal HCII Awaji protein was
suggested to have an altered amino acid sequence from position 89 and
terminate at 107, thus being composed of the NH2-terminal one fifth of
normal HCII and dysfunctional for thrombin inhibition. The molecular weight
and pI value of HCII Awaji were calculated to be 12,040 and 3.6,
respectively, without posttranslational modification. Mutagenic PCR
followed by the Tsp509I digestion showed that a half of the PCR products
derived from the propositus and his sister was cleaved, suggesting that his
sister also has the same mutant allele. Crossed-immunoelectrophoresis and
Western blot analyses of plasma and urine from the the propositus and of
plasma from his sister did not provide evidence for the existence of the
abnormal HCII, suggesting that little truncated HCII was circulating in the
patient's blood. However, stable expression assay using human kidney 293
cells transfected with the expression vector containing cDNA encoding
wild-type or Awaji-type HCII showed that mutant as well as wild-type HCII
was secreted into culture medium normally. These results suggest that the
abnormal HCII Awaji protein is secreted normally, but rapidly degraded in
the circulating blood.
Volume 87,
Issue 3,
pp. 1006-1012,
02/01/1996
Copyright © 1996 by The American Society of Hematology
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