Hyper-IgM syndrome with putative dominant negative mutation in activation-induced cytidine deaminase

Hyper-IgM immunodeficiency is an immunologic disorder characterized by normal or increased serum IgM levels and reduced serum IgG and IgA levels caused by the disruption of Ig class switching in B cells. The gene encoding activation-induced cytidine deaminase (AID) is responsible for the autosomal recessive form of hyper-IgM syndrome. To investigate the relationship between the AID gene mutation and the clinical phenotype, we analyzed the AID gene in a female Japanese patient with the autosomal recessive form of hyper-IgM syndrome. Genomic DNA and cDNA were extracted from neutrophils and analyzed by means of PCR. The AID gene was expressed as a glutathione S-transferase fusion protein. RT-PCR was performed after stimulation of the patient's PBMCs with phorbol myristate acetate and TGF-β. Despite significantly low serum IgG levels, our patient had not shown a predisposition to any severe infections, even without Ig replacement therapy. We identified a point mutation resulting in the stop codon in exon 5 of the AID gene (R190X) in the patient. No other mutations of the AID gene were detected in the patient. The same mutation was not detected in other members of her family. The mutant allele fused with the glutathione S-transferase protein was expressed stably at the same level as the normal allele. The AID gene expression in the patient was induced by phorbol myristate acetate and TGF-β. The mutation of the AID gene is assumed to be of the dominant negative form. This is the first report of a dominant negative form of the mutation in vivo.