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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

Simmonds, Rachel E.; Zöller, Bengt LU ; Ireland, Helen; Thompson, Elizabeth; García De Frutos, Pablo LU ; Dahlbäck, Björn LU and Lane, David A. (1997) In Blood 89(12). p.4364-4370
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
binding protein, complement component C4b, protein S, adolescent, adult, aged, article, child, clinical article, controlled study, female, gene mutation, genotype, human, male, phenotype, priority journal, protein S deficiency
in
Blood
volume
89
issue
12
pages
7 pages
publisher
American Society of Hematology
external identifiers
  • scopus:1842287995
ISSN
0006-4971
language
English
LU publication?
yes
id
92902f8a-a5b3-4d1f-abd3-8bd1fa353cdc
date added to LUP
2017-10-19 15:31:51
date last changed
2017-11-07 09:46:06
@article{92902f8a-a5b3-4d1f-abd3-8bd1fa353cdc,
  abstract     = {<p>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.</p>},
  author       = {Simmonds, Rachel E. and Zöller, Bengt and Ireland, Helen and Thompson, Elizabeth and García De Frutos, Pablo and Dahlbäck, Björn and Lane, David A.},
  issn         = {0006-4971},
  keyword      = {binding protein,complement component C4b,protein S,adolescent,adult,aged,article,child,clinical article,controlled study,female,gene mutation,genotype,human,male,phenotype,priority journal,protein S deficiency},
  language     = {eng},
  month        = {06},
  number       = {12},
  pages        = {4364--4370},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {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},
  volume       = {89},
  year         = {1997},
}