The PROC gene, located on chromosome 2q14.3, encodes a vitamin K-dependent plasma glycoprotein. This protein is an essential plasma anticoagulant produced from the liver; it remains inactive until it cleaves to its activated form by the thrombin-thrombomodulin complex. The activated protein regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids. Defects in this protein are the cause of protein C deficiency, an important risk factor of hereditary thrombophilia.
The PROC gene consists of eight coding exons, and spans approximately 10.8 kb in the genomic DNA. About 270 different mutations within this gene have been identified in patients with protein C deficiency.
Mutations that cause protein C deficiency type I result in reduced levels of protein C. While protein C deficiency type II is caused by mutations that result in the production of an altered protein C with reduced activity.
Abu-Amero et al. (2003) reported a nine-month-old Saudi boy with severe homozygous protein C deficiency. The boy was born to consanguineous parents after an uneventful pregnancy at 39 weeks. Using PCR and sequencing, a novel homozygous CCTG duplicate nucleotide in exon 9 of the protein C gene was identified in the patient. This insertion resulted in a frame-shift mutation, generating a prematurely truncated protein. Both parents were heterozygous for the same mutation.
Alsultan et al., (2016) described two first-degree cousins affected with perinatal intracranial hemorrhage and subsequent severe thrombosis. The first case was a 10-year-old girl who presented with seizures and intracranial hemorrhage at 13 days of age. At the age of 4 months, she had multiple thrombotic lesions over both hands and feet. At 9 years of age, both protein C amidolytic activity and protein C antigen were low, 61% (nl 70–140%) and 57% (nl 70– 140%), respectively. The second case was a 2-year-old boy who presented in the first week of life with massive subacute hemorrhage in the brain parenchyma and upper spinal canal. At the age of 4 months he underwent a ventriculoperitoneal shunt because of hydrocephalus, and post operatively he had a thrombotic lesion in his left foot. At 10 months of age protein C amidolytic activity and protein C antigen were 59% and 73%, respectively. Both cases suffered from blindness and severe permanent neurological deficit. Using Exome sequencing a homozygous variant in exon 9 of PROC gene c.811 C>T was identified in both patients. The C>T polymorphism leads to the R229W amino acid change of the serine protease domain.
Al-Hamed et al. (2016) described a 4-year-old Saudi boy with severe Protein C deficiency. As a neonate, he suffered from purpura fulminans and severe disseminated intravascular coagulation. The patient’s symptoms were treated with protein C concentrate. A genetic screen revealed a novel homozygous splice site mutation in intron 8 of the PROC gene (c.796+3A>T). The parents and two sisters were found to be heterozygous for the mutation, while the proband’s brother was homozygous for the normal genotype. Reverse transcription studies found that the mutation resulted in exon skipping and the creation of a pseudogene within an intron. The mutation was not found in 550 ethnically-matched controls. It was also noted that the GT and AG positions adjacent to the donor and acceptor splice sites were highly conserved.
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