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

Genes & Immunity volume 10, pages 433–445 (2009)Cite this article

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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Acknowledgements

We are indebted to the patients and their family members who contributed to this study. This work was supported by Grants 1R01 AR050078, 1R01 AR054459 from the NIAMS, NIAID, NIDDK and the Office of the Director, the National Institutes of Health, and by a pilot grant from the Lupus Foundation of America.

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Authors and Affiliations

  1. Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA

    Y L Wu & C Y Yu

  2. Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH, USA

    Y L Wu & C Y Yu

  3. Laboratoire d’Immunogenetique Moleculaire, Universite Louis Pasteur, Strasbourg Cedex, France

    G Hauptmann

  4. Service de Dermatologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France

    M Viguier

  5. Department of Pediatrics, The Ohio State University, Columbus, OH, USA

    C Y Yu

  6. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, USA

    C Y Yu

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  1. Y L Wu
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Correspondence to C Y Yu.

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Wu, Y., Hauptmann, G., Viguier, M. et al. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immun 10, 433–445 (2009). https://doi.org/10.1038/gene.2009.10

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