title: Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries.
abstract: BACKGROUND
  The aetiology of atypical haemolytic uraemic syndrome (aHUS) is, in contrast to classical, Shiga-like toxin induced HUS in children, largely unknown. Deficiency of human complement factor H and familial occurrence led to identification of the factor H gene (FH1) as the susceptibility gene, but the frequency and relevance of FH1 mutations are unknown.
  
  
  METHODS
  We established a German registry for aHUS and analysed in all patients and 100 controls the complete FH1 gene by single strand confirmational polymorphism and DNA sequencing. In addition, complement C3 and factor H serum levels were assayed. Demographic data at onset of aHUS and follow up were compared for the mutation positive and negative groups.
  
  
  RESULTS
  Of 111 patients with aHUS (68 female, 43 male, mean age 33 years) 14% had FH1 germline mutations, including two of eight patients with familial aHUS. For each of these eight patients, both parents were tested, and we were able to trace the mutation for five cases. In the other three cases (one with the mutation 3749 C/T, one with 3200 T/C, and one with 3566+1 G/A), we could not detect the mutation in either parent, although paternity was proven by genetic fingerprinting, suggesting that these subjects have new mutations. C3 was decreased in five mutation carriers but also in two non-carriers, and factor H was decreased in none of the carriers, but elevated in six carriers and 15 non-carriers. Clinical parameters including associated medications and diseases, and outcome of aHUS and of post-aHUS kidney transplantation were similar in the mutation positive and negative groups.
  
  
  CONCLUSIONS
  FH1 germline mutations occur with considerable frequency in patients with aHUS. Hypocomplementaemia is not regularly associated with a germline mutation, and factor H serum levels can even be elevated. Screening for FH1 mutations contributes to the classification of aHUS.
authors.affiliation: Department of Nephrology, Albert-Ludwigs-University, Freiburg, Germany. beumann@mm41.ukl.uni-freiburg.de
authors.forename: H P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: M
authors.initials: M
authors.lastname: Salzmann
authors.forename: B
authors.initials: B
authors.lastname: Bohnert-Iwan
authors.forename: T
authors.initials: T
authors.lastname: Mannuelian
authors.forename: C
authors.initials: C
authors.lastname: Skerka
authors.forename: D
authors.initials: D
authors.lastname: Lenk
authors.forename: B U
authors.initials: BU
authors.lastname: Bender
authors.forename: M
authors.initials: M
authors.lastname: Cybulla
authors.forename: P
authors.initials: P
authors.lastname: Riegler
authors.forename: A
authors.initials: A
authors.lastname: Königsrainer
authors.forename: U
authors.initials: U
authors.lastname: Neyer
authors.forename: A
authors.initials: A
authors.lastname: Bock
authors.forename: U
authors.initials: U
authors.lastname: Widmer
authors.forename: D A
authors.initials: DA
authors.lastname: Male
authors.forename: G
authors.initials: G
authors.lastname: Franke
authors.forename: P F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D000328:Adult; D001317:Austria; D003176:Complement C3 / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005858:Germany; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000150:complications / Q000235:genetics*; D006801:Humans; D007558:Italy; D007676:Kidney Failure, Chronic / Q000150:complications / Q000628:therapy; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012042:Registries / Q000706:statistics & numerical data; D013557:Switzerland
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H; D004247:DNA