title: Somatic mutation of human immunoglobulin V genes in the X-linked HyperIgM syndrome.
abstract: Somatic mutation of Ig variable regions occurs prominently in germinal centers, but it has been debated whether the mutation process initiates in germinal centers or is activated before germinal center entry of B cells. We have analyzed for the presence of somatic mutation in Ig gene rearrangements of the nonpolymorphic human VH6 gene in the X-linked HyperIgM syndrome, which is associated with defective CD40 ligand expression and absence of germinal centers and generation of memory B lymphocytes. IgM and rare IgG VH6 productive rearrangements were isolated from PBL of patients with X-linked HyperIgM syndrome. Although the majority of both the IgM and IgG VH6 rearrangements had a germline VH6 sequence, 7 of 102 VH6 IgM and 1 of 6 IgG rearrangements had a mutated VH6 gene. The mutation frequency (mutations/bp) was 1.4% with a range of 2-9 mutations per clone, a mutation frequency lower, however, than that observed in IgM (3.2%) and IgG (5.4%) VH6 rearrangements of normal individuals. These results suggest that somatic mutation may be initiated in a CD40 ligand-independent pathway before entry of B cells into germinal centers, but fails to achieve the high mutation frequency observed in the presence of germinal centers.
authors.affiliation: Department of Pediatrics, Microbiology, and Immunology, University of Rochester School of Medicine and Dentistry, New York 14642.
authors.forename: Y W
authors.initials: YW
authors.lastname: Chu
authors.forename: E
authors.initials: E
authors.lastname: Marin
authors.forename: R
authors.initials: R
authors.lastname: Fuleihan
authors.forename: N
authors.initials: N
authors.lastname: Ramesh
authors.forename: F S
authors.initials: FS
authors.lastname: Rosen
authors.forename: R S
authors.initials: RS
authors.lastname: Geha
authors.forename: R A
authors.initials: RA
authors.lastname: Insel
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis / Q000235:genetics; D001327:Autoimmune Diseases / Q000150:complications / Q000209:etiology; D001483:Base Sequence; D019013:CD40 Antigens; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000150:complications / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D008969:Molecular Sequence Data; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014960:X Chromosome / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D012333:RNA, Messenger