Molecular basis of selective IgG2 deficiency. The mutated membrane-bound form of gamma2 heavy chain caused complete IGG2 deficiency in two Japanese siblings.

Patients with IgG2 deficiency have recurrent sinopulmonary infections caused by Pneumococcus and Hemophilus. Hereditary and selective IgG2 deficiency was suspected in two Japanese siblings whose serum IgG2 levels were under detection limits, while other serum levels of immunoglobulin subclasses were within normal ranges. Expression level of spontaneous germline Cgamma2 transcript was normal, but that of the spontaneous mature Cgamma2 transcript was greatly decreased in the patients' PBMCs, suggesting the presence of a defect at or after the class switch to Cgamma2. We sequenced the Cgamma2 gene region, and in both patients a homozygous one-base insertion (1793insG) was present in exon 4 of the Cgamma2 gene, just upstream from the alternative splice site for M exons. The mutant membrane-bound gamma2 heavy chain loses the transmembrane domain and the evolutionarily conserved cytoplasmic domain. Considering several lines of evidence showing that intact expression of the membrane-bound heavy chain is essential for a normal response of B cells and production of secreted immunoglobulin in mice, we concluded that 1793insG is responsible for selective and complete IgG2 deficiency in these two siblings. This is the first documentation of a mutation in human selective IgG2 deficiency.