ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura

• Published in: Human mutation Vol. 31; no. 1; pp. 11 - 19
• Main Authors: Lotta, Luca A, Garagiola, Isabella, Palla, Roberta, Cairo, Andrea, Peyvandi, Flora
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 2010; John Wiley & Sons, Inc
• Subjects: ADAM Proteins - deficiency; ADAM Proteins - genetics; ADAMTS13; ADAMTS13 Protein; Adult; Genetic Variation; Genotype; Humans; Infant, Newborn; Mutation; Phenotype; Polymorphism, Genetic; Purpura, Thrombotic Thrombocytopenic - congenital; Purpura, Thrombotic Thrombocytopenic - genetics; Purpura, Thrombotic Thrombocytopenic - physiopathology; TTP; Upshaw-Schulman syndrome; USS; Young Adult
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21143

Congenital thrombotic thrombocytopenic purpura (TTP) (also known as Upshaw-Schulman syndrome, USS) is a rare, life-threatening disease characterized by thrombocytopenia and microangiopathic hemolytic anemia, associated with the deficiency of the von Willebrand factor-cleaving protease (ADAMTS13) due to mutations in the corresponding gene. The spectrum of clinical phenotype in congenital TTP is wide, encompassing neonatal-onset disease and adult-onset disease, forms with a single disease episode and chronic-relapsing forms. We review ADAMTS13 gene variants associated with inherited ADAMTS13 deficiency and congenital TTP. To date, 76 mutations of ADAMTS13 are reported in the literature. Missense mutations, which constitute nearly 60% of ADAMTS13 mutations, preferentially localize in the 5′-half of the gene encoding the N-terminal half of the protein, where the domains that are indispensable for ADAMTS13 catalytic function are situated. In vitro expression studies in cell cultures have shown that defects in protein secretion and catalytic activity are the main mechanisms responsible for the deficiency of ADAMTS13 in congenital TTP patients. Even if data from the literature suggest the existence of genotype-phenotype correlations, a clear relationship between the type and the effect of ADAMTS13 genetic defects with disease manifestations remains to be established. Hum Mutat 30:1-9, 2009.