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.

Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

“…The father of the affected individuals died from pancreatic carcinoma at the age of 65, and the mother is alive and well at the age of 80. In our original study (4), all of the affected members of family 1 shared a haplotype inherited from their father limited by the markers D1S212 and D1S245. This Ϸ32-megabase region contains the gene for MCP.…”

“…Family 1. Family 1 from Belgium has been described (26) and was one of three families used in our initial linkage study (4). Three male siblings were affected at the ages of 27, 31, and 35 years.…”

Mutations of Factor H Impair Regulation of Surface-bound C3b by Three Mechanisms in Atypical Hemolytic Uremic Syndrome

“…The syndrome leads ultimately to endstage renal disease with a high mortality rate (2). In aHUS cases point mutations have been found in complement components C3, factor B, CD46, factor I, and factor H (FH), all of which play a role in the activation or control of the alternative pathway (3)(4)(5)(6)(7)(8). More than half of the mutations have been found to originate in the HF1 gene that encodes FH and FH-like protein 1.…”

Disease-associated Sequence Variations Congregate in a Polyanion Recognition Patch on Human Factor H Revealed in Three-dimensional Structure

“…Tight regulation and targeting of the complement system is thus essential to good health. The recent association of genetic variations in complement regulatory proteins with pathologies of the kidney (4,5) and eye (6 -9) is an important development. It not only offers additional insights into the role played by complement in pathophysiological mechanisms, but it opens up the possibility of tailoring prevention and intervention according to genotype.…”

“…Many aHUS patients carry mutations in the regulators of complement activation (RCA) gene cluster of chromosome 1q32. Between 10 and 30% of aHUS patients are heterozygous for mutations in the complement regulatory protein, factor H (fH) (4,5), most of which map to its C-terminal region (15)(16)(17). Many of the remaining patients carry mutations elsewhere in the RCA gene cluster (18).…”