Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Dysregulation of the alternative complement pathway on endothelial surfaces underlies disease pathogenesis. Membrane cofactor protein (CD46) is a transmembrane complement regulator that acts as a cofactor for factor I–mediated cleavage of C3b and C4b, protecting host cells from complement‐mediated damage.
Genetic evidence supports an autosomal dominant inheritance with incomplete penetrance for CD46 in aHUS. Rare heterozygous and homozygous mutations in CD46 have been identified in at least four unrelated families, with segregation of disease in multiple affected relatives, and an estimated six unrelated probands carrying CD46 mutations in cohort studies ([PMID:15121049]). Segregation analyses revealed co‐segregation of CD46 splice‐site and missense variants with aHUS in pedigrees, although healthy carriers demonstrate incomplete penetrance ([PMID:18514989]).
The CD46 variant spectrum in aHUS comprises missense substitutions, splice-site mutations, small deletions, and premature stop codons. A recurrent intronic change, c.286+2T>G, occurs in ~13 of 485 patients, often with T (p.Cys64Phe) impair C3b binding and cofactor activity, facilitating complement overactivation on host cells ([PMID:26559391]). Loss-of-function alleles (e.g., c.175C>T (p.Arg59Ter)) further illustrate the importance of intact CD46 function in complement regulation.
Experimental studies demonstrate that CD46 isoforms with distinct O-glycosylation domains differentially protect against classical and alternative complement activation. BC-isoforms cleave C4b more efficiently than C-isoforms, and pathogenic mutations cause intracellular retention or reduced surface expression of CD46, compromising complement regulation ([PMID:8666815]). Ex vivo endothelial assays show excessive complement deposition when CD46 is deficient, recapitulating microvascular injury in aHUS.
Incomplete penetrance of CD46 variants is influenced by additional genetic modifiers and risk haplotypes, including CFH-H3 and CFHR1-CFHR3 deletions. Multiple hits, such as co-carriage of CFH variants or anti-FH autoantibodies, are often required for clinical manifestation, underscoring a multi-factorial genetic architecture in aHUS.
Integrated genetic and functional data establish CD46 as a strong aHUS predisposition gene. Identification of CD46 mutations informs risk stratification, supports complement blockade with eculizumab, and guides family counseling. Given incomplete penetrance, asymptomatic carriers warrant monitoring under complement‐activating conditions. Clinicians should consider CD46 testing in all aHUS patients for personalized management.
Key Take-home: CD46 mutations confer a strong, autosomal dominant risk for aHUS via impaired cofactor activity, with functional assays and complement inhibitors guiding diagnosis and therapy.
Gene–Disease AssociationStrongMultiple families (4) and ~6 unrelated probands with segregating CD46 variants; concordant functional data Genetic EvidenceStrongOver 50 rare CD46 variants in ~120 probands across cohorts; demonstrated segregation and recurrent splice variant c.286+2T>G ([PMID:33224962]) Functional EvidenceModerateIn vitro assays showing impaired C3b/C4b cofactor activity, isoform studies, and ex vivo complement deposition assays |