GENETIC-STUDIES INTO INHERITED AND SPORADIC HEMOLYTIC-UREMIC SYNDROME

Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Altho ugh familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that mw 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 o f 26 cM located at 1q32 segregated with the disease (Z max 3.94). We d emonstrate that the gene for factor II lies within the region. Subsequ ent mutation analysis of the factor II gene has revealed two mutations in patients with HUS. In an individual with the sporadic/ relapsing f orm of the disease we have found a mutation comprising a deletion, sub sequent frame shift and premature stop codon leading to half normal le vels 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 li kely to alter structure and hence function of the factor H protein. Fa ctor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of thes e findings and previous reports of HUS in patients with factor H defic iency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.