A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans
Akihisa Sawada, … , Keiichi Ozono, Junichi Hara
Akihisa Sawada, … , Keiichi Ozono, Junichi Hara
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1707-1713. https://doi.org/10.1172/JCI18937.
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Categories: Article Immunology

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 helixes 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

Akihisa Sawada, Yoshihiro Takihara, Ji Yoo Kim, Yoshiko Matsuda-Hashii, Sadao Tokimasa, Hiroyuki Fujisaki, Keiko Kubota, Hiroko Endo, Takashi Onodera, Hideaki Ohta, Keiichi Ozono, Junichi Hara

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Figure 1

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Detection of the translocation site. (a) Spectral karyotyping (SKY) FISH...
Detection of the translocation site. (a) Spectral karyotyping (SKY) FISH. (b) FISH. Red boxes indicate probes hybridized to chromosome 20 and der20; yellow boxes indicate probes hybridized to chr_20 and der9. PAC dJ890O15 was hybridized to chromosome 20, der20, and der9. (c) Genomic Southern blot hybridization with the ET1033 probe. The arrowhead indicates the mutation. (d) Genomic PCR products from chromosome 20, der20, and der9. cen, centromere; tel, telomere. (e) Sequences of the translocation site. Chr_9, chromosome 9; chr_20, chromosome 20.