title: Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome.
abstract: Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura. We investigated whether genetic variations in the ADAMTS13 gene partially explain the reduced activity known to occur in some patients with aHUS. We measured complement activity and ADAMTS13 function, and completed mutation screening of multiple complement genes and ADAMTS13 in a large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least 1 nonsynonymous change in ADAMTS13, and in 38% of patients, multiple ADAMTS13 variations were found. Six of the 9 amino acid substitutions in ADAMTS13 were common single nucleotide polymorphisms; however, 3 variants-A747V, V832M, and R1096H- were rare, with minor allele frequencies of 0.0094%, 0.5%, and 0.32%, respectively. Reduced complement and ADAMTS13 activity (<60% of normal activity) were found in over 60% and 50% of patients, respectively. We concluded that partial ADAMTS13 deficiency is a common finding in aHUS patients and that genetic screening and functional tests of ADAMTS13 should be considered in these patients.
authors.affiliation: Division of Internal Medicine, Benign Hematology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shuju
authors.initials: S
authors.lastname: Feng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Eyler
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tara
authors.initials: T
authors.lastname: Maga
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kroll
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Smith
authors.forename: Vahid
authors.initials: V
authors.lastname: Afshar-Kharghan
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000235:genetics*; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000328:Adult; D000483:Alleles; D065766:Atypical Hemolytic Uremic Syndrome; D001323:Autoantibodies / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D017242:Complement Factor H / Q000276:immunology; D004247:DNA / Q000235:genetics; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D011993:Recombinant Fusion Proteins; D017242:Complement Factor H; D004247:DNA; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human