Scientific background:

Summary: The gene product cleaves von Willebrand factor. A non-functioning protease triggers excessive intravascular clotting and diseases as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

Gene: The ADAMTS13 gene also known as von Willebrand factor-cleaving protease (VWFCP) belongs to the family of metalloproteases. The gene is about 37 kb in size and consists of 29 exons. Two splice variants are described.

Pathology: The activity of the gene product responsible for von Willebrand factor cleavage in plasma predominantly derives from synthesis in the liver. Although other organs also translate the gene, physiological consequences are still unknown. The two splice variants consist of 1,427 and 842 amino acid respectively. The translation product contains a signal peptide and propeptide. The activation of the propeptide takes place in apparatus of Golgi or at the cell surface. The ready to use protease cleaves specifically large von Willebrand multimers anchored to the epithelium and hereby causes its rapid degradation. If this function is impaired, the sustaining large von Willebrand multimers induce microthrombi that are the crucial pathogenetic step in genesis of thrombotic microangiopathies.

Clinical signs: The most prominent clinical manifestations are hereditary forms of HUS and TTP. Several cases of Upshaw-Schulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura may be ascribed to mutations of this gene. Other clinical entities of reduced activity of this protease are disseminated intravascular coagulation, systemic lupus erythematosous, metastatic malignancies, liver cirrhosis, and chronic inflammation. In what extend in these disorders acquired and inherited disorders are involved in activity reduction is not clear yet.

Epidemiology: Because only few families are described so far there are not sufficient epidemiological data. Mutations of the gene seems to occur in all races.

Interpretation: If a loss-of function mutation were detected, immunosuppressive therapy could be omitted. In future, these patients are candidates for recombinant ADAMTS13 supplementation. Family consulting may also be an issue.

Test strategy: An indication exists in cases with sustained and recurrent disease. Especially in cases where there is evidence of a family history.

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		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.
	research test	Method		Gene dosage measurements
		Turn-around time		25 working days
		Effort		medium
		Specimen		DNA
		Quality assessment		Internal quality control only
	Of the gene rearrangements, this method is useful to detect large deletions or duplications.

Literature: 

Kokame K et al. (2002) Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.
Matsumoto M et al. (2004) Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.
Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.