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 language | English |
|---|---|
| Pages (from-to) | 1542-1547 |
| Number of pages | 6 |
| Journal | Lancet |
| Volume | 362 |
| Issue number | 9395 |
| DOIs | |
| Publication status | Published - Nov 8 2003 |
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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 journal › Article
}
TY - JOUR
T1 - Familial haemolytic uraemic syndrome and an MCP mutation
AU - Noris, Marina
AU - Brioschi, Simona
AU - Caprioli, Jessica
AU - Todeschini, Marta
AU - Bresin, Elena
AU - Porrati, Francesca
AU - Gamba, Sara
AU - Remuzzi, Giuseppe
PY - 2003/11/8
Y1 - 2003/11/8
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(03)14742-3
DO - 10.1016/S0140-6736(03)14742-3
M3 - Article
C2 - 14615110
AN - SCOPUS:0242570482
VL - 362
SP - 1542
EP - 1547
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9395
ER -