Insights into hemolytic uremic syndrome: Segregation of three independent predisposition factors in a large, multiple affected pedigree

Abstract

Mutations in the complement regulators factor H, membrane cofactor protein (MCP), and factor I are associated with atypical hemolytic uremic syndrome (aHUS, MIM 235400), suggesting that the disease develops as a consequence of the inefficient protection of the renal endothelium from damage by the complement system. Incomplete penetrance of the disease in individuals carrying these mutations is, however, relatively frequent. Here, we report the identification of a large, multiple affected aHUS pedigree in which there is independent segregation of three different aHUS risk factors: a MCP missense mutation (c.-598C>T; Pro165Ser) that decreases MCP expression on the cell surface, a dinucleotide insertion in the coding sequence of factor I (c.-1610insAT) that introduces a premature stop codon in the factor I protein, and the MCPggaac SNP haplotype block that was previously shown to decrease the transcription activity from the MCP promoter. Interestingly, individuals affected by aHUS in the pedigree are only those who have inherited the three aHUS risk factors. These data show an additive effect for mutations in MCP and factor I and provide definitive support to the conclusion that aHUS results from a defective protection of cellular surfaces from complement activation. Furthermore, they help to explain the incomplete penetrance of the disease, illustrating that concurrence of multiple hits in complement regulatory proteins may be necessary to significantly impair host tissue protection and to confer susceptibility to aHUS.

Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I

“…The following mutations analyzed in this study have been previously reported in aHUS patients: C25F, P32A, N133S, H165R [32], W127x, L289x (c.893delC) [8], A222G, R299W, W468x (c.1446-1450 delTTCAC), D501N [4], R456x, W528x [7] and T520x (c.1610insAT) [31]. The M120V mutation was identified in a Caucasian patient from Saudi Arabia.…”

“…In this study, we have investigated the functional effects of 14 CFI mutations identified in aHUS patients [4,7,8,31,32]. These mutations are present in different domains: the FIMAC, CD5, LDLr1, region of unknown homology and SP domain (Fig.…”

“…In this report, 14 heterozygous mutations in the FI gene (CFI, complement factor I), previously identified by different groups [4,7,8,31,32], have been studied to determine their effects on protein expression, secretion and function. To date, only the locations of these CFI mutations and the clinical descriptions of patient symptoms have been reported.…”

“…The light chain comprises the SP domain [27]. The concentration of FI in blood is rather low, 35 mg/mL, and it is mainly produced by hepatocytes [28] but also by monocytes [29] and fibroblasts [30].In this report, 14 heterozygous mutations in the FI gene (CFI, complement factor I), previously identified by different groups [4,7,8,31,32], have been studied to determine their effects on protein expression, secretion and function. To date, only the locations of these CFI mutations and the clinical descriptions of patient symptoms have been reported.…”

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

“…However, the general consensus is that mutations of complement regulators more predispose rather than cause the thrombotic microangiopathy (Esparza-Gordillo et al, 2006;Goodship et al, 2004). In this setting, endothelial activation that occurs secondary to injury is undesirably enhanced by excessive complement activation.…”