CD46 – Hemolytic Uremic Syndrome

Membrane cofactor protein (CD46) is a ubiquitously expressed regulator of the complement system that inhibits C3b and C4b deposition on host cells. Dysregulation of complement activation is a well‐established cause of atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy characterised by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (PMID:18215115). CD46 mutations reduce cell‐surface expression or cofactor activity, leading to uncontrolled complement activation and endothelial damage.

Heterozygous CD46 variants predispose to aHUS with incomplete penetrance, often unmasked by infectious or pharmacologic triggers such as Shigella flexneri infection or cisplatin exposure (PMID:26307634, PMID:24422172). Both autosomal dominant inheritance and homozygous presentations have been reported, reflecting variable expressivity.

Familial studies identified pathogenic CD46 mutations in nine of 30 kindreds, including a two–amino‐acid deletion (c.811_816del (p.Asp271_Ser272del)) and a missense substitution (c.718T>C (p.Ser240Pro)) segregating with disease in multiple relatives (PMID:14566051; PMID:14615110). A sibling pair with a splice‐donor change (c.286+2T>G) showed marked reduction in CD46 surface expression, confirming pathogenicity (PMID:18514989).

The variant spectrum includes loss‐of‐function alleles (frameshift c.800_801del (p.Thr267fs)), splice‐site mutations (c.286+2T>G), and missense changes impairing cofactor activity (c.718T>C (p.Ser240Pro)). No single founder variant predominates, though recurrent intron‐2 splice variants are reported in multiple populations.

Functional assays in patient cells and transfectants demonstrate markedly decreased CD46 surface levels and impaired C3b inactivation for both deletion and missense mutants. Rescue of complement regulation by eculizumab underlines the mechanistic link between CD46 deficiency and endothelial injury (PMID:24422172).

Incomplete penetrance is evident from asymptomatic heterozygotes and rare homozygous carriers lacking disease manifestations, highlighting the necessity of triggers and genetic modifiers in aHUS pathogenesis (PMID:18514989).

Overall, CD46 haploinsufficiency due to heterozygous loss‐of‐function or hypomorphic variants is a definitive cause of atypical HUS. Genetic testing for CD46 variants informs diagnostic differentiation, guides eculizumab therapy, and enables family counseling. Key take-home: CD46 genetic screening is clinically actionable in aHUS, with functional assays and targeted complement inhibition improving outcomes.

References

• Annual review of pathology • 2008 • Pathogenesis of thrombotic microangiopathies. PMID:18215115
• Lancet (London, England) • 2003 • Familial haemolytic uraemic syndrome and an MCP mutation. PMID:14615110
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. PMID:14566051
• American journal of kidney diseases • 2008 • Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair. PMID:18514989
• Pediatric nephrology (Berlin, Germany) • 2015 • Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome. PMID:26307634
• Clinical kidney journal • 2013 • Cisplatin-induced haemolytic uraemic syndrome associated with a novel intronic mutation of CD46 treated with eculizumab. PMID:24422172

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