CD55-deficiency is caused by bi-allelic mutations (homozygous or compound heterozygous) in the CD55 gene. Most patients harbor loss-of-function mutations (nonsense, frameshift, splice-site), causing early truncation of the protein; missense mutations affecting critical sites for protein function and missense mutations that activate a cryptic splice-site have also been observed in CD55-deficiency patients. In cases when the pathogenicity of the mutation is not certain, CD55 protein expression analysis may be required to confirm the diagnosis.
CD55 encodes a membrane-bound complement system regulator – decay accelerating factor (DAF). DAF inhibits C3 and C5 convertases and accelerates the decay of existing ones, thus preventing complement-induced self-injury by the membrane attack complex (MAC). Loss of CD55 (DAF) leads to complement dysregulation or hyperactivation. The subsequent elevated MAC deposition on patient cells causes intestinal inflammation and injury, which manifests as PLE. In addition, studies show that CD55-deficient cells exhibit IL-10 dysfunction, which may contribute to the intestinal inflammation, and explain why some CD55-deficiency patients may be misdiagnosed with inflammatory bowel disease (IBD).