title: Genetic variations in complement factors in patients with congenital thrombotic thrombocytopenic purpura with renal insufficiency.
abstract: 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.
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.|Department of Clinical Laboratory, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Xinping
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland. johanna.kremer@insel.ch.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Kremer Hovinga
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shirotani-Ikejima
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Eura
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Honda
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.
authors.forename: Magnus Mansouri
authors.initials: MM
authors.lastname: Taleghani
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Hematology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: von Krogh
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital and University of Bern, 3010, Bern, Switzerland.|Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Mainz, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lämmle
authors.affiliation: Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Suita, Japan. miyata@ncvc.go.jp.|Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan. miyata@ncvc.go.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000071120:ADAMTS13 Protein / Q000235:genetics; D000328:Adult; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics; D003176:Complement C3 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011697:Purpura, Thrombotic Thrombocytopenic / Q000151:congenital* / Q000235:genetics*; D051437:Renal Insufficiency / Q000209:etiology* / Q000235:genetics*
chemical_list: D003176:Complement C3; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: Atypical hemolytic uremic syndrome; Complement factors; Renal insufficiency; Thrombotic thrombocytopenic purpura; Upshaw–Schulman syndrome
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