title: Aberrant splicing of the milk fat globule-EGF factor 8 (MFG-E8) gene in human systemic lupus erythematosus.
abstract: Milk fat globule-EGF factor 8 (MFG-E8) promotes the phagocytosis of apoptotic cells by serving as a bridging molecule between apoptotic cells and phagocytes. Many apoptotic cells are left unengulfed in the germinal centers of the spleen of MFG-E8(-/-) mice, which develop a human systemic lupus erythematosus (SLE)-like autoimmune disease. Here, we analyzed the MFG-E8 gene in human SLE patients, and found in two out of 322 female patients a heterozygous intronic mutation, which caused a cryptic exon from intron 6 to be included in the transcript. The cryptic exon contained a premature termination codon, generating a C-terminally truncated MFG-E8 protein. The mutant MFG-E8 was aberrantly glycosylated and sialylated, but bound to phosphatidylserine and enhanced the phagocytosis of apoptotic cells. When intravenously injected into mice, the mutant MFG-E8 was sustained longer in the blood circulation than wild-type MFG-E8. Repeated administrations of the mutant MFG-E8 protein induced the production of autoantibodies, such as anti-cardiolipin and anti-nuclear antibodies, at a lower dose than that required for the wild-type protein. These results suggested that the intronic mutation in the human MFG-E8 gene can lead to the development of SLE.
authors.affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Shinobu
authors.initials: S
authors.lastname: Nakamura
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ohmura
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D010587:Phagocytosis / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D001324:Autoantigens; C098942:MFGE8 protein, human; D008894:Milk Proteins; D012333:RNA, Messenger