Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency
The congenital form of thrombotic thrombocytopenic purpura (TTP) is caused by genetic mutations in ADAMTS13. Some, but not all, congenital TTP patients manifest renal insufficiency in addition to microangiopathic hemolysis and thrombocytopenia. We included 32 congenital TTP patients in the present study, which was designed to assess whether congenital TTP patients with renal insufficiency have predisposing mutations in complement regulatory genes, as found in many patients with atypical hemolytic uremic syndrome (aHUS). In 13 patients with severe renal insufficiency, six candidate complement or complement regulatory genes were sequenced and 11 missense mutations were identified. One of these missense mutations, C3:p.K155Q mutation, is a rare mutation located in the macroglobulin-like 2 domain of C3, where other mutations predisposing for aHUS cluster. Several of the common missense mutations identified in our study have been reported to increase disease-risk for aHUS, but were not more common in patients with as compared to those without renal insufficiency. Taken together, our results show that the majority of the congenital TTP patients with renal insufficiency studied do not carry rare genetic mutations in complement or complement regulatory genes.
KeywordsAtypical hemolytic uremic syndrome Complement factors Renal insufficiency Thrombotic thrombocytopenic purpura Upshaw–Schulman syndrome
- 10.Kremer Hovinga JA, Lämmle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Hematol Am Soc Hematol Educ Program. 2012;2012:610–6.Google Scholar
- 21.Heurich M, Martinez-Barricarte R, Francis NJ, Roberts DL, Rodriguez de Cordoba S, Morgan BP, et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci. 2011;108:8761–6.PubMedCentralCrossRefPubMedGoogle Scholar
- 30.Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, et al. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet. 2003;12:3385–95.CrossRefPubMedGoogle Scholar