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Protein CVermont: symptomatic type II protein C deficiency associated with
two GLA domain mutations
EG Bovill, JA Tomczak, B Grant, F Bhushan, E Pillemer, IR Rainville and GL Long
Department of Biochemistry, University of Vermont College of Medicine,
Burlington 05405.
This study investigates type II protein C deficiency in a family with
manifestations of both arterial and venous thrombosis. Of 64 members of the
kindred, 14 have been tested and 7 have PC deficiency. Among affected
individuals (n = 7), mean protein C levels by different assays were as
follows: enzyme-linked immunosorbent assay (ELISA), 3.8 micrograms/mL (2.1
to 4.3 micrograms/mL); amidolytic with venom activator, 115% (60% to 140%);
clotting with venom activator, 42% (23% to 59%). The mean ratio of clotting
to amidolytic assays for the affected individuals was 0.37 compared with a
normal range of 0.8 to 1.2. Thus, the affected individuals have normal
total protein C and their activated protein C has a normal active site
assessed by chromogenic substrate; however, they have markedly diminished
clotting activity. Immunoassay and chromatography data suggested an
abnormality of carboxylation in the gamma carboxyglutamic acid (Gla)
domain. Polymerase chain reaction amplification and direct DNA sequencing
of exon 2 from genomic DNA of affected individuals showed two nucleotide
substitutions. One of the mutations (A----C) results in Glu20----Ala,
thereby eliminating a site for vitamin K-dependent gamma-carboxylation. The
other substitution (G----A) results in a Val34----Met mutation. DNA
sequencing of the other exons from affected individuals has shown no
further difference from that of the wild-type gene. The former mutation
also removes a Bgl II restriction endonuclease site, which has allowed us
to confirm the mutation in affected individuals by direct digestion and
Southern hybridization of genomic DNA from family members. This is the
first reported family with documented Gla domain mutations in the protein C
gene.
Volume 79,
Issue 6,
pp. 1456-1465,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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