title: Mutations in Bruton's tyrosine kinase impair IgA responses.
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 CD19(low) and CD19(normal) fractions were observed, and both included naïve and memory B cells. Calcium influx and phospholipase Cγ2 phosphorylation upon IgM stimulation were marginally impaired in CD19(low), 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.
authors.affiliation: Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8510, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Mitsuiki
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Sophinus J W
authors.initials: SJ
authors.lastname: Bartol
authors.forename: Christina
authors.initials: C
authors.lastname: Grosserichter-Wagener
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kosaka
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics* / Q000473:pathology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D059472:Exome; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017098:IgA Deficiency / Q000235:genetics* / Q000473:pathology; D007070:Immunoglobulin A / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D007070:Immunoglobulin A; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human