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Molecular genetic analysis of severe protein C deficiency

Millar, D S; Johansen, B; Berntorp, Erik LU ; Minford, A; Bolton-Maggs, P; Wensley, R; Kakkar, V; Schulman, S; Torres, A and Bosch, N, et al. (2000) In Human Genetics 106(6). p.646-653
Abstract
Severe protein C deficiency is a rare, early onset, venous thrombotic condition that is inherited as an autosomal recessive trait. The protein C (PROC) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro splicing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a... (More)
Severe protein C deficiency is a rare, early onset, venous thrombotic condition that is inherited as an autosomal recessive trait. The protein C (PROC) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro splicing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a good prognostic indicator of the age of onset or clinical severity of thrombotic symptoms. Other factors may thus complicate the relationship between genotype and clinical phenotype. Indeed, in two patients, the inheritance of either one or two Factor V Leiden alleles in addition to two PROC gene lesions could have served to precipitate the thrombotic events. No association was however apparent between clinical severity and the possession of a particular promoter polymorphism genotype. Despite the absence of a clear genotype-phenotype relationship, the molecular genetic analysis of the severe recessive form of protein C deficiency potentiates both the counselling of affected families and the provision of antenatal exclusion diagnosis. (Less)
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publication status
published
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Human Genetics
volume
106
issue
6
pages
646 - 653
publisher
Springer
external identifiers
  • pmid:10942114
  • scopus:0033917013
ISSN
1432-1203
DOI
10.1007/s004390050038
language
English
LU publication?
yes
id
d5c1a228-6edf-4734-b302-d5a9188d138c (old id 1117561)
date added to LUP
2008-06-27 12:05:22
date last changed
2017-08-13 04:30:36
@article{d5c1a228-6edf-4734-b302-d5a9188d138c,
  abstract     = {Severe protein C deficiency is a rare, early onset, venous thrombotic condition that is inherited as an autosomal recessive trait. The protein C (PROC) genes of nine unrelated individuals with severe protein C deficiency were sequenced yielding a total of 13 different lesions. Eight of these were novel, including a gross gene deletion, three missense mutations, two micro-deletions, a splicing mutation and a single base-pair substitution in the HNF-3 binding site in the PROC gene promoter. Evidence for the pathogenicity of the mutations detected was obtained by molecular modelling, in vitro splicing assay and reporter gene assay. Neither the plasma protein C activity level nor the nature of the PROC gene lesions detected were found to be a good prognostic indicator of the age of onset or clinical severity of thrombotic symptoms. Other factors may thus complicate the relationship between genotype and clinical phenotype. Indeed, in two patients, the inheritance of either one or two Factor V Leiden alleles in addition to two PROC gene lesions could have served to precipitate the thrombotic events. No association was however apparent between clinical severity and the possession of a particular promoter polymorphism genotype. Despite the absence of a clear genotype-phenotype relationship, the molecular genetic analysis of the severe recessive form of protein C deficiency potentiates both the counselling of affected families and the provision of antenatal exclusion diagnosis.},
  author       = {Millar, D S and Johansen, B and Berntorp, Erik and Minford, A and Bolton-Maggs, P and Wensley, R and Kakkar, V and Schulman, S and Torres, A and Bosch, N and Cooper, D N},
  issn         = {1432-1203},
  language     = {eng},
  number       = {6},
  pages        = {646--653},
  publisher    = {Springer},
  series       = {Human Genetics},
  title        = {Molecular genetic analysis of severe protein C deficiency},
  url          = {http://dx.doi.org/10.1007/s004390050038},
  volume       = {106},
  year         = {2000},
}