SNPs in ADAMTS13.
ABSTRACT The multidomain metalloprotease ADAMTS13 limits thrombus formation via the cleavage of large multimeric forms of von Willebrand factor. Deficiency of functional ADAMTS13 is associated with a number of disease pathologies including thrombotic thrombocytopenic purpura, cardiovascular disease and inflammation. To date, deficiency is known to result from mutations in the ADAMTS13 gene or from inhibitory and non-neutralizing antibodies. The exact contributory effect of genetic variation in ADAMTS13 on observable pathology is unclear, and specifically, polymorphisms of ADAMTS13 have not been the focus of much systematic study. Here we have amassed an up-to-date collection of ADAMTS13 polymorphisms described in the literature and from the National Center for Biotechnology Information's SNP database. This article considers the effect that these polymorphisms may have on the expression and function of ADAMTS13 and speculates on their relevance in future therapies based on pharmacogenomics.
SourceAvailable from: Rafal Bartoszewski[Show abstract] [Hide abstract]
ABSTRACT: The most common disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the out-of-frame deletion of 3 nucleotides (CTT). This mutation leads to the loss of phenylalanine-508 (ΔF508) and a silent codon change (SCC) for isoleucine-507 (I507-ATC→ATT). ΔF508 CFTR is misfolded and degraded by endoplasmic reticulum-associated degradation (ERAD). We have demonstrated that the I507-ATC→ATT SCC alters ΔF508 CFTR mRNA structure and translation dynamics. By comparing the biochemical and functional properties of the I507-ATT and I507-ATC ΔF508 CFTR, we establish that the I507-ATC→ATT SCC contributes to the cotranslational misfolding, ERAD, and to the functional defects associated with ΔF508 CFTR. We demonstrate that the I507-ATC ΔF508 CFTR is less susceptible to the ER quality-control machinery during translation than the I507-ATT, although 27°C correction is necessary for sufficient cell-surface expression. Whole-cell patch-clamp recordings indicate sustained, thermally stable cAMP-activated Cl(-) transport through I507-ATC and unstable function of the I507-ATT ΔF508 CFTR. Single-channel recordings reveal improved gating properties of the I507-ATC compared to I507-ATT ΔF508 CFTR (NPo=0.45±0.037 vs. NPo=0.09±0.002; P<0.001). Our results signify the role of the I507-ATC→ATT SCC in the ΔF508 CFTR defects and support the importance of synonymous codon choices in determining the function of gene products.-Lazrak, A., Fu, L., Bali, V., Bartoszewski, R., Rab, A., Havasi, V., Keiles, S., Kappes, J., Kumar, R., Lefkowitz, E., Sorscher, E. J., Matalon, S., Collawn, J. F., Bebok, Z. The silent codon change I507-ATC→ATT contributes to the severity of the ΔF508 CFTR.The FASEB Journal 08/2013; DOI:10.1096/fj.13-227330 · 5.48 Impact Factor