Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus
Y L Wu1, G Hauptmann, M Viguier
1Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Insights
Complete C4 deficiency, a major SLE risk factor, was studied in two families. Genetic mutations in C4A and C4B were identified, highlighting C4
Area of Science:
- Immunogenetics
- Molecular Biology
- Human Genetics
Background:
- Complete deficiency of complement C4 (C4) is a significant genetic risk factor for systemic lupus erythematosus (SLE).
- C4 is part of the RP-C4-CYP21-TNX (RCCX) module within the human leukocyte antigen (HLA) complex, known for variations in copy number and gene size.
- Understanding these variations is crucial for comprehending SLE pathogenesis.
Observation:
- Two North-African families with complete C4 deficiency and SLE were investigated.
- Patients presented with early-onset SLE, photosensitive rashes, anti-Ro/SSA antibodies, renal disease, and high antinuclear antibody titers.
- Genetic analysis revealed specific RCCX module structures (monomodular and bimodular) in the studied patients.
Findings:
- A C>T transition causing an R540X nonsense mutation in C4A was identified in one patient (1P).
- A 4-bp insertion leading to a Y1537X nonsense mutation in both C4A and C4B was found in the other patient (2P).
- These mutations disrupt C4 protein function, linking genetic defects to SLE.
Implications:
- The study underscores the critical role of C4 proteins in protecting against SLE, even in the absence of common HLA-DR3 and HLA-DR2 risk haplotypes.
- Identifying specific C4 gene mutations provides insights into the molecular mechanisms underlying SLE development.
- These findings could inform genetic counseling and the development of targeted therapies for SLE patients with C4 deficiency.
Abstract:
Complete deficiency of complement C4 is among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). C4 is a constituent of the RP-C4-CYP21-TNX (RCCX) module in the human leukocyte antigen (HLA) that exhibits inter-individual copy-number and gene-size variations. Here, we studied two North-African families with complete C4 deficiency and SLE. The first included a Moroccan male SLE patient (1P) and a sibling, who were both homozygous for HLA-A*02 B*17 DRB1*07. The second had an Algerian female SLE patient (2P) homozygous for HLA-A*01 B*17 DRB1*13. Early SLE disease onset, the presence of photosensitive rashes, anti-Ro/SSA, renal disease and high titers of antinuclear antibodies were the common features of complete C4 deficiency. Southern blot analyses showed that 1P had monomodular RCCX with a long C4A, whereas 2P had bimodular RCCX with one long C4A and one short C4B. Genomic DNA fragments for these mutant genes were amplified and sequenced. A C>T transition that created the R540X nonsense mutation in C4A was found in 1P. An identical 4-bp insertion that generated the Y1537X nonsense mutation was discovered in both C4A and C4B of 2P. The high concordance of SLE and C4 deficiency among patients with non-DR3 and non-DR2 haplotypes underscores the importance of C4 proteins in the protection against SLE.
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