Scientific background:

Summary: This protein plays an important role in taming blood coagulation, so inactivating mutations bring about a higher risk of intravascular coagulation, increased risk of thrombosis.

Gene: The gene can be abreviated by PROS1. Its locus is on chromosom 3 (3p11.1-q11.2). Size is about 95kb and it consists of 15 exons.

Pathology: The protein product is a vitamin K dependent cofactor for activated protein C. It is produced in liver, endothelial and cells.

Clinical signs: Clinically important are thromboembolic diseases. Cerebral infarktion before age of 45 are suspect too. An aquired protein S deficiency must be excluded.

Epidemiology: The prevalence of protein C deficiency is 0,03-0,13%. This figure is much higher among patients with thromboembolic diseases (1-5%) and it might rise up to 15% among younger patient. In Patients with Cerebral infarctions occurring without apparent reason before age of 45 this figure is even 20%.

Interpretation: The mutation is rare but the relative risk for thromboembolic diseases is is 8,2.

Test strategy: Patient with biochemical evidence of Protein S deficiency when a secondary reason is excluded. Family screening if a family member is a carrier.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Tsuda H et al. (2002) Four missense mutations identified in the protein S gene of thrombosis patients with protein S deficiency: effects on secretion and anticoagulant activity of protein S.
Douay X et al. (1998) Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke.
Watkins PC et al. (1988) The gene for protein S maps near the centromere of human chromosome 3.
Duchemin J et al. (1995) The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency.
Hoskins J et al. (1987) Cloning and characterization of human liver cDNA encoding a protein S precursor.