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Molecular Basis of a Selective C1s Deficiency Associated with Early Onset Multiple Autoimmune Diseases¹

Marie-Agnès Dragon-Durey^2,3,*,, Pierre Quartier^2,, Véronique Frémeaux-Bacchi^*,, Jacques Blouin^*, Claire de Barace, Anne-Marie Prieur, Laurence Weiss^*, and Wolf-Herman Fridman^*,¶

^* Service d’Immunologie Biologique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité 430, Immunopathologie Humaine, Hôpital Broussais, Paris, France; Unité d’Immuno-Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; Service de Pédiatrie, Hôpital de Saint Brieuc, Saint Brieuc, France; and ^¶ Institut National de la Santé et de la Recherche Médicale, Unité 255, Université Pierre et Marie Curie, les Cordeliers, Paris, France

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto’s thyroiditis, and autoimmune hepatitis. This patient’s complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.