Download Genetic Mutations Affecting Complement Factor I in Atypical

Genetic Mutations Affecting Complement Factor I in Atypical Haemolytic Uraemic Syndrome
Introduction
Genomic disorders affecting the genes encoding factor H and the factor H related proteins are well
described in atypical haemolytic uraemic syndrome (aHUS). In contrast, genomic disorders affecting the
gene (CFI) encoding factor I are extremely rare, and have not been previously reported in aHUS. Here,
we describe a novel heterozygous deletion of CFI associated with aHUS and present the CFI variants
found in the Newcastle cohort of aHUS patients.
Methods
Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to screen for
CFI variants and genomic disorders, respectively. C3 and C4 were measured by rate nephelometry. Factor
H and factor I were measured by radial immunodiffusion. Complement auto-antibodies were screened by
ELISA. The breakpoint of the heterozygous deletion involving CFI was defined by microarray, high
density SNP genotyping and long range PCR.
Results
A 36 year old male presented with renal failure, thrombocytopaenia and schistocytes on blood film. A
renal biopsy showed thrombotic microangiopathy. Factor I concentration was low. No abnormalities were
detected on Sanger sequencing of CFI but further analysis revealed a heterozygous 875,324bp deletion at
4q25 encompassing CFI and ten other genes. The patient undergoes peritoneal dialysis and is now listed
for kidney transplantation with eculizumab prophylaxis. We undertook MLPA in 7 other patients with
low factor I levels and normal Sanger sequencing of CFI, but did not identify any deletions.
In the Newcastle aHUS cohort we have identified 32 different CFI variants in 56 patients. Twenty-seven
of the 32 different variants are non-synonymous; the amino acid changes are shown in crystal structure
where possible (Fig. 1). Factor I levels in patients with CFI variants are shown (Fig. 2). Thirty-nine
percent (22/56) carry, in addition, either a rare variant in another complement gene and/or antibodies
against factor H.
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Conclusion
Genomic disorders affecting CFI in aHUS are extremely rare. However, given the major clinical
implications, particularly with respect to transplantation, CFI MLPA should be undertaken as part of
routine screening in aHUS.