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Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus.

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.
AuthorsY L Wu, G Hauptmann, M Viguier, C Y Yu
JournalGenes and immunity (Genes Immun) Vol. 10 Issue 5 Pg. 433-45 (Jul 2009) ISSN: 1476-5470 [Electronic] England
PMID19279649 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Complement C4
  • HLA-A Antigens
Topics
  • Black People (genetics)
  • Complement C4 (deficiency, genetics, immunology)
  • Consanguinity
  • Female
  • HLA-A Antigens (genetics)
  • Humans
  • Lupus Erythematosus, Systemic (genetics, immunology)
  • Male
  • Pedigree

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