Selective IgG2 deficiency due to a point mutation causing abnormal splicing of the Cγ2 gene

Abstract

The mechanism underlying selective IgG subclass deficiency is largely unknown in humans. We have previously reported the acquisition of a complete IgG2 deficiency in a leukemia patient after bone marrow transplantation. Southern blot analysis showed a deletion including the Cγ2 and Cγ4 genes on one chromosome in the donor, suggesting that the remaining Cγ2 gene allele was silent. In the patient and his two IgG2 deficient brothers, the silent Cγ2 gene showed both germ-line transcription and switch recombination and no structural defects were found in the intronic promoter or the switch region of the gene. However, an A→G transition in the fourth nucleotide in the 5′ portion of intron 1 was identified. Transfection of artificial constructs into the human B cell lines demonstrated that this A→G transition inactivated the normal splice site, and instead, a cryptic splice site in the CH1 exon was used in RNA post-transcriptional processing, leading to a 16 bp deletion of the γ2 CH1 exon. This aberrantly spliced RNA that is mostly derived from germ-line transcription in vivo was also detected in both homozygous and heterozygous individuals carrying this mutation. These findings suggest a novel genetic mechanism as the cause of IgG subclass deficiency in selected patients. © 2005 The Japanese Society for Immunology.