title: Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation.
abstract: Sequence analysis of the ADAMTS13 locus of 2 patients with hereditary thrombotic thrombocytopenic purpura (TTP) revealed the homozygous presence of 4 single nucleotide polymorphisms (SNPs) (R7W, Q448E, P618A, A732V) and a rare missense mutation (R1336W). Analysis of the individual effect of any amino acid exchanges showed that several sequence variations can interact with each other, thereby altering the phenotype of ADAMTS13 deficiency. Introduction of polymorphisms R7W, Q448E, and A732V had no or only minor effects on ADAMTS13 secretion. In contrast, P618A, R1336W, and the A732V-P618A combination strongly reduced ADAMTS13-specific activity and antigen levels. Surprisingly, R7W and Q448E were positive modifiers of ADAMTS13 secretion in the context of P618A and A732V but neither could rescue the severely reduced specific activity conferred by P618A. However, in the context of R1336W, polymorphisms R7W and Q448E enhanced the detrimental effect of the missense mutation and led to undetectable enzyme activity. We show that dependent on the sequence context, the same polymorphisms might be either positive or negative modifiers of gene expression. Our results might therefore be widely relevant to understanding the influence of polymorphisms on the phenotypic expression of complex diseases.
authors.affiliation: Baxter Bioscience, Department of Discovery Research, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plaimauer
authors.forename: Jakob
authors.initials: J
authors.lastname: Fuhrmann
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mohr
authors.forename: Waltraud
authors.initials: W
authors.lastname: Wernhart
authors.forename: Katharina
authors.initials: K
authors.lastname: Bruno
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferrari
authors.forename: Christian
authors.initials: C
authors.lastname: Konetschny
authors.forename: Gerhard
authors.initials: G
authors.lastname: Antoine
authors.forename: Manfred
authors.initials: M
authors.lastname: Rieger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000071120:ADAMTS13 Protein; D002460:Cell Line; D005192:Family Health; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics*; D014162:Transfection
chemical_list: D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human