title: A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans.
abstract: A girl with congenital agammaglobulinemia and minor facial anomalies lacked B cells in peripheral blood: karyotypic analysis of white blood cells showed balanced translocation, t(9;20)(q33.2;q12). In the current study, we isolated a novel gene, leucine-rich repeat-containing 8 (LRRC8), at the translocation site on chromosome 9. It has four transmembrane helices with one isolated and eight sequentially located leucine-rich repeats (LRRs) and constitutes a new protein family. It is expressed on T cells as well as on B-lineage cells. Translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains located close to the C-terminal. The truncated form of the LRRC8 gene is transcribed with sequences from the noncoding region adjacent to the truncated seventh LRR. Protein products derived from the truncated gene are coexpressed on white blood cells with the intact LRRC8 protein from the untranslocated allele. Transplantation experiments with murine bone marrow cells that were forced to express the truncated LRRC8 show that expression of the truncated protein inhibited B cell development. These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development.
authors.affiliation: Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sawada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.forename: Ji Yoo
authors.initials: JY
authors.lastname: Kim
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Matsuda-Hashii
authors.forename: Sadao
authors.initials: S
authors.lastname: Tokimasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fujisaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Kubota
authors.forename: Hiroko
authors.initials: H
authors.lastname: Endo
authors.forename: Takashi
authors.initials: T
authors.lastname: Onodera
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohta
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.forename: Junichi
authors.initials: J
authors.lastname: Hara
mesh_terms: D000293:Adolescent; D000361:Agammaglobulinemia / Q000209:etiology / Q000235:genetics*; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins