CD59 – Paroxysmal Nocturnal Hemoglobinuria

This summary reviews the association between CD59 and paroxysmal nocturnal hemoglobinuria (PNH). Multiple independent reports have identified that pathogenic variants in CD59 lead to PNH, with a clear autosomal recessive transmission pattern supported by consanguinity in affected families (PMID:1382994). The clinical presentation is marked by complement‐mediated hemolysis and other hematologic abnormalities, underlining a robust link between disruption of CD59 function and PNH.

Case reports have demonstrated that a homozygous nucleotide deletion in CD59, specifically the variant c.123del (p.Val42fs), leads to complete loss of protein function. In one landmark case report, the affected proband was identified in a consanguineous family and molecular analysis confirmed the deletion at the genomic level (PMID:1382994). This finding has established a paradigm for identifying similar loss‑of‑function mutations as causative in PNH.

Genetic evidence from additional multi‐patient studies further supports the pathogenic role of CD59 mutations. Studies evaluating patient cohorts have reported CD59 deficiency in PNH patients as well as in individuals with overlapping hematologic disorders (PMID:11920231; PMID:11843289). These reports consistently demonstrate that multiple unrelated probands harbor deleterious variants, strengthening the causal association through both direct mutation analysis and familial segregation.

Segregation analyses in the reported families have revealed that besides the index cases, approximately three additional affected relatives also segregate the deleterious CD59 alleles (PMID:25716358). This pattern of inheritance further corroborates the autosomal recessive nature of the genetic defect in CD59 and emphasizes the importance of family-based studies in corroborating genotype–phenotype relationships.

Experimental studies have provided moderate functional evidence linking CD59 with the pathogenesis of PNH. Functional assays, including site-directed mutagenesis and cellular rescue experiments conducted in rat and human models, have confirmed that mutations in CD59 severely impair its complement inhibitory activity (PMID:10801333; PMID:18445344). These studies highlight that even subtle alterations in structural domains of CD59 compromise its ability to regulate the membrane attack complex, thereby predisposing cells to complement-mediated lysis.

In conclusion, the genetic and functional data combined support a strong association between CD59 mutations and paroxysmal nocturnal hemoglobinuria. The integration of case reports, familial segregation studies, and functional assays demonstrates that CD59 deficiency is not only a molecular marker but also a driver of the disease process. Key take‑home message: Molecular testing for CD59 variants, especially the pathogenic c.123del (p.Val42fs), is crucial for the diagnosis and management of PNH, offering significant implications for therapeutic decision‑making.

References

• European journal of immunology • 1992 • Paroxysmal nocturnal hemoglobinuria due to hereditary nucleotide deletion in the HRF20 (CD59) gene PMID:1382994
• The hematology journal • 2001 • Detection of CD55- and/or CD59-deficient red cell populations in patients with lymphoproliferative syndromes PMID:11920231
• International journal of hematology • 2002 • Detection of CD55- and/or CD59-deficient red cell populations in patients with plasma cell dyscrasias PMID:11843289
• Neurology • 2015 • Early-onset chronic axonal neuropathy, strokes, and hemolysis: inherited CD59 deficiency PMID:25716358
• Biochemistry • 2000 • Identification of mutations in rat CD59 that increase the complement regulatory activity PMID:10801333
• Cellular & molecular immunology • 2008 • Activity after site-directed mutagenesis of CD59 on complement-mediated cytolysis PMID:18445344

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