Mutations in Bruton’s tyrosine kinase impair IgA responses

Noriko Mitsuiki, Xi Yang, Sophinus J.W. Bartol, Christina Grosserichter-Wagener, Yoshiyuki Kosaka, Hidetoshi Takada, Kohsuke Imai, Hirokazu Kanegane, Shuki Mizutani, Mirjam van der Burg, Menno C. van Zelm, Osamu Ohara, Tomohiro Morio

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in Bruton’s tyrosine kinase (BTK), and is characterized by markedly decreased numbers of blood B cells and an absence of all immunoglobulin isotypes. We performed whole exome sequencing in a male pediatric patient with dysgammaglobulinemia with IgA deficiency. Genetic analysis revealed a BTK missense mutation (Thr316Ala). To investigate whether a BTK mutation underlay this antibody deficiency with marked decrease of IgA in this patient, we performed functional analyses of B cells and phagocytes, and molecular analyses of somatic hypermutation and class switch recombination. The BTK missense mutation resulted in B cells with reduced BTK and high IgM expression. Equal proportions of CD19low and CD19normal fractions were observed, and both included naïve and memory B cells. Calcium influx and phospholipase Cγ2 phosphorylation upon IgM stimulation were marginally impaired in CD19low, but not in CD19+ B cells. Similar to XLA patients, IgA transcripts showed low SHM levels, whereas IgG transcripts were hardly affected. Our analyses suggest that the BTK mutation likely underlies the disease in this case, and that hypomorphic BTK mutations can result in normal circulating B cell numbers, but specifically impair IgA responses.

Original languageEnglish
Pages (from-to)305-313
Number of pages9
JournalInternational Journal of Hematology
Volume101
Issue number3
DOIs
Publication statusPublished - Mar 6 2015

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Immunoglobulin A
B-Lymphocytes
Mutation
Missense Mutation
Immunoglobulin M
Dysgammaglobulinemia
IgA Deficiency
Exome
Phospholipases
Immunoglobulin Isotypes
Phagocytes
Agammaglobulinaemia tyrosine kinase
Genetic Recombination
Blood Cells
Cell Count
Immunoglobulin G
Phosphorylation
Pediatrics
Calcium
Antibodies

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Mitsuiki, N., Yang, X., Bartol, S. J. W., Grosserichter-Wagener, C., Kosaka, Y., Takada, H., ... Morio, T. (2015). Mutations in Bruton’s tyrosine kinase impair IgA responses. International Journal of Hematology, 101(3), 305-313. https://doi.org/10.1007/s12185-015-1732-1

Mutations in Bruton’s tyrosine kinase impair IgA responses. / Mitsuiki, Noriko; Yang, Xi; Bartol, Sophinus J.W.; Grosserichter-Wagener, Christina; Kosaka, Yoshiyuki; Takada, Hidetoshi; Imai, Kohsuke; Kanegane, Hirokazu; Mizutani, Shuki; van der Burg, Mirjam; van Zelm, Menno C.; Ohara, Osamu; Morio, Tomohiro.

In: International Journal of Hematology, Vol. 101, No. 3, 06.03.2015, p. 305-313.

Research output: Contribution to journalArticle

Mitsuiki, N, Yang, X, Bartol, SJW, Grosserichter-Wagener, C, Kosaka, Y, Takada, H, Imai, K, Kanegane, H, Mizutani, S, van der Burg, M, van Zelm, MC, Ohara, O & Morio, T 2015, 'Mutations in Bruton’s tyrosine kinase impair IgA responses', International Journal of Hematology, vol. 101, no. 3, pp. 305-313. https://doi.org/10.1007/s12185-015-1732-1
Mitsuiki N, Yang X, Bartol SJW, Grosserichter-Wagener C, Kosaka Y, Takada H et al. Mutations in Bruton’s tyrosine kinase impair IgA responses. International Journal of Hematology. 2015 Mar 6;101(3):305-313. https://doi.org/10.1007/s12185-015-1732-1
Mitsuiki, Noriko ; Yang, Xi ; Bartol, Sophinus J.W. ; Grosserichter-Wagener, Christina ; Kosaka, Yoshiyuki ; Takada, Hidetoshi ; Imai, Kohsuke ; Kanegane, Hirokazu ; Mizutani, Shuki ; van der Burg, Mirjam ; van Zelm, Menno C. ; Ohara, Osamu ; Morio, Tomohiro. / Mutations in Bruton’s tyrosine kinase impair IgA responses. In: International Journal of Hematology. 2015 ; Vol. 101, No. 3. pp. 305-313.
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