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Genetic and phenotypic analysis of a large (122-member) protein S-
deficient kindred provides an explanation for the familial coexistence of
type I and type III plasma phenotypes
RE Simmonds, B Zoller, H Ireland, E Thompson, PG de Frutos, B Dahlback and DA Lane
Department of Haematology, Charing Cross and Westminster Medical School,
London, UK.
Protein S deficiency is a known risk factor for thrombosis. The coexistence
of phenotypic type I (reduction in total and free antigen) and type III
(reduction in free antigen only) protein S deficiencies in 14 of 18
families was recently reported. We investigated the cause of this
phenotypic variation in the largest of these families (122 family members,
including 44 affected individuals) using both molecular genetic and
phenotypic analysis. We have identified a sole causative mutation
(Gly295Val) in three family members representative of the variable
phenotype. Complete cosegregation of the mutation with reduced free protein
S antigen levels was found, regardless of the total antigen level. Analysis
of phenotypic data showed high correlations between total protein S antigen
and age in both normal and protein S- deficient family members,
irrespective of gender. Free protein S antigen levels were not influenced
by age, a finding explained by an association between beta-chain containing
C4b-binding protein (C4bBP- beta+) antigen levels and age. We propose that
the identified Gly295Val mutation causes quantitative, or type I, protein S
deficiency, and that as age increases the total protein S antigen level
normalizes with respect to the reference plasma pool, giving rise to a type
III protein S-deficient phenotype.
Volume 89,
Issue 12,
pp. 4364-4370,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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