title: 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.
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Y L
authors.initials: YL
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Hauptmann
authors.forename: M
authors.initials: M
authors.lastname: Viguier
authors.forename: C Y
authors.initials: CY
authors.lastname: Yu
mesh_terms: D044383:Black People / Q000235:genetics; D003181:Complement C4 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D003241:Consanguinity; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008297:Male; D010375:Pedigree
chemical_list: D003181:Complement C4; D015234:HLA-A Antigens