Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

von Willebrand factor-cleaving protease

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.

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.

Gene Structure

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.

Phenotype

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.

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.

Test Strategy

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

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.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Thrombotic Thrombocytopenic Purpura
ADAMTS13
Hemolytic-Uremic Syndrome
ADAMTS13
C3
C4BPA
C4BPB
CD46
CFB
CFH
CFHR1
CFHR2
CFHR3
CFHR4
CFHR5
CFI
CLU
DGKE
Methylmalonic aciduria
Methylmalonic aciduria and homocystinuria cblC
MMACHC
Methylmalonic aciduria and homocystinuria cblD
MMADHC
Methylmalonic aciduria type mut
MUT
PIGA
PLG
THBD

References:

1.

Nürnberger J et al. (2009) Eculizumab for atypical hemolytic-uremic syndrome.

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2.

Kokame K et al. (2002) Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.

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3.

Matsumoto M et al. (2004) Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.

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Update: Sept. 26, 2018