Molecular genetic analysis of severe protein C deficiency

Research output: Contribution to journalArticle

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.

Details

Authors
  • D S Millar
  • B Johansen
  • Erik Berntorp
  • A Minford
  • P Bolton-Maggs
  • R Wensley
  • V Kakkar
  • S Schulman
  • A Torres
  • N Bosch
  • D N Cooper
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
Pages (from-to)646-653
JournalHuman Genetics
Volume106
Issue number6
Publication statusPublished - 2000
Publication categoryResearch
Peer-reviewedYes