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Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome

发布于：2013年7月14日    文字：【大】【中】【小】

Blood. 2013 Jul 11. [Epub ahead of print]

Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome.

Feng S, Eyler SJ, Zhang Y, Maga T, Nester CM, Kroll MH, Smith RJ, Afshar-Kharghan V.

Source

Division of Internal Medicine, Benign Hematology, University of Texas, M.D. Anderson Cancer Center, Houston, TX, United States;

Abstract

Complement dysregulation leads to atypical hemolytic uremic syndrome (aHUS), while ADAMTS13 deficiency causes thrombotic thrombocytopenic purpura (TTP). 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 ina large cohort of aHUS patients. In over 50% of patients we identified complement gene mutations. Surprisingly, 80% of patients also carried at least one non-synonymous 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 three 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.

补体调节异常可导致不典型溶血尿毒综合征(aHUS)的发生，而ADAMTS13缺陷导致血栓性血小板减少性紫癜(TTP)的发生。我们研究了ADAMTS13基因异常是否可以解释在部分aHUS患者中出现的ADAMTS13活性的下降。我们检测了一个较大的aHUS队列人群的补体水平、ADAMTS13功能，并检测了多个补体以及ADAMTS13的基因背景。在50%以上的aHUS患者中检测到了补体基因的突变。有趣的是，80%患者出现了一个ADAMTS13基因的非同义的改变。在38%患者中出现了各种ADAMTS13的变异。在9个引起ADAMTS13的氨基酸改变的基因变异中，有6个为常见的SNP位点，有3个- A747V, V832M, and R1096H-是少见的SNP位点，他们的次等位基因频率分别为0.0094%, 0.5%, 和 0.32%。补体及ADAMTS13活性的降低分别出现在60%和50%的患者中。我们推测，ADAMTS13的缺陷在aHUS患者中较常见，在这些患者中应该考虑进行ADAMTS13的活性和基因的检测。