Factor H gene variants in Japanese: Its relation to atypical hemolytic uremic syndrome

Abstract

Mutations and polymorphisms of factor H gene (FH1) are known to be closely involved in the development of atypical hemolytic uremic syndrome (aHUS). Several groups have identified disease risk mutations and polymorphisms of FH1 for the development of aHUS, and have investigated frequencies of aHUS in a number of ethnic groups. However, such studies on Japanese populations are limited. In the present study, we analyzed FH1 in Japanese aHUS patients and healthy volunteers, and examined whether those variants impacted on a tendency for the development of aHUS in Japanese populations. Similar to previous studies, we found that a high frequency of FH1 mutations, located in exon 23 of FH1, encodes short consensus repeat 20 in C-terminal end of factor H molecule in patients with aHUS (40%), but not in healthy volunteers. Interestingly, no significant differences in frequency of well-known disease risk polymorphisms for aHUS were observed between healthy volunteers and aHUS patients. Our results suggested that although FH1 mutations relates to the development of Japanese aHUS in accordance with other ethnic studies, other factor may be required for factor H polymorphism to be a risk factor of Japanese aHUS.

Introduction

Hemolytic uremic syndrome (HUS) is a microvasculature disorder characterized by the triad of microangiopathic hemolytic anemia, renal failure, and thrombocytopenia, and is mainly caused by the enterocolitis with Shiga toxin-producing Eschericia coli of the serotype O157:H7 (Karmali et al., 1983, Karmali et al., 1985). This form, known as typical HUS, has a good prognosis, and not often affects family members (Kaplan et al., 1998, Ault, 2000, Sánchez-Corral and Melgosa, 2010). In contrast, atypical HUS (aHUS), characterized by the absence of any infection (e.g., Shiga toxin-producing E. coli, Shigella dysenteriae, and Streptococcus pneumoniae) and its associated-diarrhea, tends to relapse and have a poor prognosis (Kaplan et al., 1998, Ault, 2000, Sánchez-Corral and Melgosa, 2010), and has been classified as either sporadic or familial (Kaplan et al., 1975). Approximately 50% of patients with aHUS have mutations in the genes encoding complement regulatory proteins [e.g., factor H, membrane cofactor protein (MCP or CD46), factor I, factor B, thrombomodulin, and C3] (Atkinson et al., 2005, Caprioli et al., 2006, Delvaeye et al., 2009). In particular, the gene coding factor H, FH1, is known to be the most frequently affected in the development of aHUS (Caprioli et al., 2006).

Factor H, a 150-kDa plasma glycoprotein predominantly produced in the liver, consists of 20 homologous units of about 60 amino acid residues each, known as short consensus repeats (SCRs) or the complement control protein units (Ault, 2000). Factor H plays a critical role in the regulation of the alternative complement activation pathway; i.e., this complement component is a cofactor for serine protease factor I in cleaving C3b to its inactive form (C3bi) and accelerates decay of the alternative complement pathway C3bBb convertase complex (Weiler et al., 1976, Whaley and Ruddy, 1976, Pangburn et al., 1977). Several reports demonstrated that anomalous function of factor H, attributed to the mutations in FH1, affects the complementary activation and the pathogenesis of aHUS (Pangburn, 2002, Sánchez-Corral et al., 2004, Ferreira and Pangburn, 2007). Actually, Saunders et al. (2006) previously demonstrated that the majority of FH1 mutations in patients with aHUS causes either single amino acid exchange or premature translation interruption within SCR 20, a domain which contains recognition sites for cell surface ligands, and consequently the binding avidity of factor H (to C3b, heparin, or endothelial cells) is reduced.

To date, several linkage analyses have revealed that FH1 is a candidate gene for aHUS, because its mutations or polymorphisms could be frequently detectable in aHUS patients (Caprioli et al., 2001, Caprioli et al., 2003, Richards et al., 2001, Neumann et al., 2003, Esparza-Gordillo et al., 2005). However, to our knowledge, the frequency of FH1 mutations and polymorphisms and their relation to aHUS in Japanese subjects have not been well-defined.

We designed this study with an aim to characterize factor H and its impact on the clinical phenotype in Japanese aHUS patients. Further, we analyzed the frequency of FH1 mutations and polymorphisms in Japanese patients with aHUS, their family members, and healthy volunteers to clarify its relevance to the pathogenesis of aHUS.