Combined occurrence of a heterozygous missense mutation in the protein C gene and allelic exclusion of one protein S allele leading to severe venous thrombosis

Individuals with more than one defect in the natural anticoagulant system e xhibit an increased risk for thrombosis. We report on a family with two cas es of combined protein C (PROC) and protein S (PROS) deficiency, five cases of isolated PROC deficiency Type I, and two cases of isolated PROS deficie ncy Type I. PROC and PROS deficiency were documented by functional and immu nologic tests. The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at n t 8490, leading to an exchange of alanine 259 by threonine. The mutation wa s present in family members with PROC deficiency. The carriers of the isola ted PROC mutation were asymptomatic at ages of 4, 7, 10, 11, and 80 years. The combination of the PROC mutation with a PROS deficiency in two family m embers triggered venous thromboembolism at age 31 and 6 years, respectively . The PROS deficiency was associated with complete exclusion of one PROS al lele. Two family members with isolated PROS deficiency are still asymptomat ic at age 21 and 9 years, respectively. Our findings in this family suggest that the heterozygous mutation at codon 259 of the PROC gene represents a mild thrombotic risk factor and only confers a high thrombotic risk in comb ination with a second defect, such as the complete exclusion of one PROS al lele. (C) 2001 Elsevier Science Ltd. All rights reserved.