Factor H gene variants in Japanese: Its relation to atypical hemolytic uremic syndrome
Highlights
► We analyze FH1 in Japanese aHUS. ► Japanese aHUS have FH1 mutations in its exon 23. ► Interestingly, healthy Japanese have the well-known disease risk polymorphisms for aHUS. Although FH1 mutations relates to the development of Japanese aHUS, 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.
Section snippets
Subjects
DNA samples were extracted from whole peripheral blood leukocytes obtained from aHUS patients [n = 10, 3 men and 7 women; age range 1–40 years (mean ± SE, 19 ± 5 years)], the family members (for the pedigree analysis), and healthy volunteers [n = 15, 3 men and 12 women; age range 26–58 years (mean ± SE, 41 ± 3 years)] using QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. We also used 32 healthy volunteer's sera for hemolytic assay. As described previously (
Clinical features of patients with aHUS
Clinical features and genetic findings of FH1 of 10 patients with aHUS were summarized in Table 2, Table 3, respectively.
Patient 1 (A-6). We analyzed for factor H status using patient's serum, obtained after 1-yr from the episode. Serum factor H level was also significantly decreased (75% of healthy volunteer's serum, p < 0.01). The heterozygous G3717A mutation, and heterozygous polymorphisms of C-257T, A2089G, G2881T, and G1492A were found in FH1. Anti-factor H antibody was not detected. Other
Discussion
In the present study, we identified FH1 mutation in 4 of 10 aHUS patients. All of those mutations, located in exon 23 of FH1, encode SCR 20 (3 Arg1215Gln mutations and 1 Ser1191Leu mutation). Previous studies demonstrated that the majority of the mutations associated with aHUS are clustered at the SCR 20 in C-terminal end of factor H molecule, which plays a critical role as both C3 (C3d fragment)- and heparin-binding sites (Blackmore et al., 1998, Ault, 2000, Caprioli et al., 2001). Three of
Competing interests
None.
Ethical approval
The study was approved by the ethics committee of Shinsyu University (approval No., 221).
Guarantor
KY.
Contributorship
KY has designed and supervised the project, SM, YH, MH, and KM have carried out the project, SM has written the first draft of the manuscript, NF, YK and SK have been the laboratory methods consultants, and KK and TH commented on drafts of the manuscript.
Acknowledgements
We gratefully acknowledge Dr Toshiko Kumagai and Dr Mitsutoshi Sugano (Department of Laboratory Medicine, Shinshu University Hospital) for their advices and encouragement. This work was partially supported by Nagano Society for the Promotion of Science.
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