title: Genetic studies into inherited and sporadic hemolytic uremic syndrome.
abstract: Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.
authors.affiliation: Department of Medicine, University of Newcastle upon Tyne, England, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Warwicker
authors.forename: T H
authors.initials: TH
authors.lastname: Goodship
authors.forename: R L
authors.initials: RL
authors.lastname: Donne
authors.forename: Y
authors.initials: Y
authors.lastname: Pirson
authors.forename: A
authors.initials: A
authors.lastname: Nicholls
authors.forename: R M
authors.initials: RM
authors.lastname: Ward
authors.forename: P
authors.initials: P
authors.lastname: Turnpenny
authors.forename: J A
authors.initials: JA
authors.lastname: Goodship
mesh_terms: D000328:Adult; D001483:Base Sequence; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004276:DNA, Satellite / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification
chemical_list: C493495:CFH protein, human; D004276:DNA, Satellite; D012333:RNA, Messenger; D017242:Complement Factor H; D003165:Complement System Proteins