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 journalArticle

247 Citations (Scopus)

Abstract

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
JournalLancet
Volume362
Issue number9395
DOIs
Publication statusPublished - Nov 8 2003

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CD46 Antigens
Hemolytic-Uremic Syndrome
Mutation
Complement Factor H
Complement System Proteins
Complement C1
Complement Receptors
Thrombotic Thrombocytopenic Purpura
Nonsense Codon
Complement Activation
Genes
Registries
Diarrhea
Endothelial Cells
Kidney
Polymerase Chain Reaction
Wounds and Injuries
Serum

ASJC Scopus subject areas

  • Medicine(all)

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Familial haemolytic uraemic syndrome and an MCP mutation. / Noris, Marina; Brioschi, Simona; Caprioli, Jessica; Todeschini, Marta; Bresin, Elena; Porrati, Francesca; Gamba, Sara; Remuzzi, Giuseppe.

In: Lancet, Vol. 362, No. 9395, 08.11.2003, p. 1542-1547.

Research output: Contribution to journalArticle

Noris, M, Brioschi, S, Caprioli, J, Todeschini, M, Bresin, E, Porrati, F, Gamba, S & Remuzzi, G 2003, 'Familial haemolytic uraemic syndrome and an MCP mutation', Lancet, vol. 362, no. 9395, pp. 1542-1547. https://doi.org/10.1016/S0140-6736(03)14742-3
Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003 Nov 8;362(9395):1542-1547. https://doi.org/10.1016/S0140-6736(03)14742-3
Noris, Marina ; Brioschi, Simona ; Caprioli, Jessica ; Todeschini, Marta ; Bresin, Elena ; Porrati, Francesca ; Gamba, Sara ; Remuzzi, Giuseppe. / Familial haemolytic uraemic syndrome and an MCP mutation. In: Lancet. 2003 ; Vol. 362, No. 9395. pp. 1542-1547.
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