title: Fate of the mutated IgG2 heavy chain: lack of expression of mutated membrane-bound IgG2 on the B cell surface in selective IgG2 deficiency.
abstract: IgG2 deficiency is clinically characterized by sinopulmonary infections caused by pneumococcus and Hemophilus. We reported homozygous one-base insertion (1793insG) in the C(gamma)2 gene in two Japanese siblings in whom serum IgG2 levels were under detection limits. The 1793insG was present in exon 4, just upstream from the alternative splice site for M exons; the result being a complete amino acid change in transmembrane and cytosolic parts of membrane-bound gamma2 heavy chain (m gamma 2HC). To determine why this mutation caused selective and complete IgG2 deficiency, we constructed expression vectors of normal and mutant membrane-bound chimeric IgG heavy chain cDNAs. Stable transformants, Ag8N-L and Ag8M-L, expressing either normal and mutant chimeric IgG heavy chain with light chain respectively were obtained using P3X63Ag8653 as recipient cells. Of the Ag8N-L, 22.1% were surface IgG+; however, none of the Ag8M-L were surface IgG+. Addition of an anti-human IgG antibody induced cell death of Ag8N-L and we considered that the expressed chimeric IgG protein on Ag8N-L might function as the Ig receptor for signal transduction. However, Ag8M-L did not express mutant IgG on its surface nor did it secrete this mutant into culture medium. The mutant chimeric IgG protein was rapidly degraded within Ag8M-L. Thus, the mutated IgG2 heavy chain in our patient could not be expressed on the cell surface because of loss of the transmembrane domain and the evolutionally conserved cytoplasmic domain. In humans, B cells expressing surface IgG are indispensable for secretion of IgG.
authors.affiliation: Department of Paediatrics, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Terada
authors.forename: H
authors.initials: H
authors.lastname: Kaneko
authors.forename: T
authors.initials: T
authors.lastname: Fukao
authors.forename: H
authors.initials: H
authors.lastname: Tashita
authors.forename: A L
authors.initials: AL
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Takemura
authors.forename: N
authors.initials: N
authors.lastname: Kondo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000138:chemical synthesis; D006801:Humans; D017099:IgG Deficiency / Q000235:genetics* / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D012333:RNA, Messenger / Q000032:analysis; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins