Molecular genetic analysis of severe protein C deficiency

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.

Familial thrombotic risk based on the genetic background of Protein C Deficiency in a Portuguese Study

“…The mother developed thrombophlebitis during puerperium and the infant's sister remained asymptomatic until 20 yrs of age. It is known that the inheritance of F5L and PROC gene lesions is associated with a cumulative thrombotic risk . In this case, the inheritance of a single allele with PROC mutation along with the two F5L alleles was a potentially critical precipitating event in the early‐onset thrombotic episodes in the affected infant.…”

“…Heterozygous individuals have an approximately sevenfold increased risk of VT compared with normal individuals . The rare form of PC deficiency, severe homozygous (or compound heterozygous), was first described as a cause of neonatal purpura fulminans resulting in rapid death caused by massive venous thrombosis . However, a number of adult patients with very low or undetectable plasma PC levels have been found; they exhibit milder symptoms and/or a later onset of the disease .…”

Neonatal asphyxia and renal failure as the presentation of non-inherited protein C deficiency

“…Genetic PC deficiency arises from a gross deletion in patients with no PROC mutation. 11 However, the qualitative and quantitative abnormality of PC molecule associated with de novo heterozygous PC deficiency was excluded by 102% of PC activity at the age of 10 months. The blood samples at diagnosis showed undetectable PIVKA-II and normal FVII activity.…”

Symptomatic type 1 protein C deficiency caused by a de novo Ser270Leu mutation in the catalytic domain

“…The present work describes a de novo Ser270Leu mutation of the catalytic domain of protein C associated with venous thrombosis and type 1 protein C deficiency. The same mutation has recently been reported (Millar et al , 2000), is listed in a database (Reitsma et al , 1995) and is present in a family with two compound heterozygote members also carrying a splice site mutation. From the available data, it is not possible to conclude whether the Ser270Leu mutation is the cause or just linked to the cause of the plasma protein C deficiency.…”