Familial haemolytic uraemic syndrome and an MCP mutation

Marina Noris, Simona Brioschi, Jessica Caprioli, Marta Todeschini, Elena Bresin, Francesca Porrati, Sara Gamba, Giuseppe Remuzzi

Research output: Contribution to journalArticlepeer-review


Background: Mutations in factor H (HF1) have been reported in a consistent number of diarrhoea-negative, non-Shiga toxin-associated cases of haemolytic uraemic syndrome (D-HUS). However, most patients with D -HUS have no HF1 mutations, despite decreased serum concentrations of C3. Our aim, therefore, was to assess whether genetic abnormalities in other complement regulatory proteins are involved. Methods: We screened genes that encode the complement regulatory proteins - ie, factor H related 5, complement receptor 1, and membrane cofactor protein (MCP) - by PCR-single-strand conformation polymorphism (PCR-SSCP) and by direct sequencing, in 25 consecutive patients with D-HUS, an abnormal complement profile, and no HF1 mutation, from our International Registry of Recurrent and Familial HUS/TTP (HUS/thrombotic thrombocytopenic purpura). Findings: We identified a heterozygous mutation in MCP, a surface-bound complement regulator, in two patients with a familial history of HUS. The mutation causes a change in three aminoacids at position 233-35 and insertion of a premature stop-codon, which results in loss of the transmembrane domain of the protein and severely reduced cell-surface expression of MCP. Interpretation: Results of previous studies on HF1 indicate an association between HF1 deficiency and D-HUS. Our findings of an MCP mutation in two related patients suggest that impaired regulation of complement activation might be a factor in the pathogenesis of genetic forms of HUS. MCP could be a second putative candidate gene for D -HUS. The protein is highly expressed in the kidney and plays a major part in regulation of glomerular C3 activation. We propose, therefore, that reduced expression of MCP in response to complement-activating stimuli could prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury.

Original languageEnglish
Pages (from-to)1542-1547
Number of pages6
Issue number9395
Publication statusPublished - Nov 8 2003

ASJC Scopus subject areas

  • Medicine(all)


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