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International Immunology Advance Access published online on November 29, 2004
International Immunology, doi:10.1093/intimm/dxh192
© 2004 by The Japanese Society for Immunology
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Received August 10, 2004
Accepted October 29, 2004

Article

Selective IgG2 deficiency due to a point mutation causing abnormal splicing of the C{gamma}2 gene

Yaofeng Zhao 1*, Qiang Pan-Hammarström 1, Zhihui Zhao 1, Sicheng Wen 1, and Lennart Hammarström 1

1 Division of Clinical Immunology, Department of Laboratory Medicine, F79, Karolinska University Hospital Huddinge, Karolinska Institute, SE-141 86, Stockholm, Sweden

* To whom correspondence should be addressed.
Yaofeng Zhao, E-mail: Yaofeng.Zhao{at}labmed.ki.se


  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 C{gamma}2 and C{gamma}4 genes on one chromosome in the donor, suggesting that the remaining C{gamma}2 gene allele was silent. In the patient and his two IgG2 deficient brothers, the silent C{gamma}2 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 {gamma}2 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.

Keywords: class switch recombination; germ-line transcription; immunoglobulin.
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