Mutations in Btk in Patients with Presumed X-Linked Agammaglobulinemia

Background: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton's Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations.Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient.Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes.Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.

X-linked agammaglobulinemia

Mutation Testing

10.1080/1744666x.2018.1413349

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Citations (16)

Identification and Characterization of a Novel SH3-Domain Binding Protein, Sab, Which Preferentially Associates with Bruton's Tyrosine Kinase (Btk)

Biochemical and Biophysical Research Communications (1998)

M. Matsushita Tomoki Yamadori Seishi Kato Yoshihiro Takemoto Jouji Inazawa

Immunoprecipitation

X-linked agammaglobulinemia

Protein kinase domain

10.1006/bbrc.1998.8420

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Citations (64)

Bruton's Tyrosine Kinase (BTK) is present in normal platelets, and its absence identifies patients with X-Linked Agammaglobulinemia (XLA) and carrier females

Chiaki Watanabe Takeshi Futatani Yoshihiro Baba Satoshi Tsukada A. Oda

Bruton's Tyrosine Kinase (BTK) Is Present in Normal Platelets, and Its Absence Identifies Patients with X-Linked Agammaglobulinemia (XLA) and Carrier Females

X-linked agammaglobulinemia

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Citations (0)

Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA)

Frontiers in bioscience (2000)

Mauno Vihinen

X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency disorder that is caused by a differentiation block leading to almost complete absence of B lymphocytes and plasma cells. The affected protein is a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase (Btk). Btk along with Tec, Itk, Bmx and Txk belong to a distinct family of protein kinases. These proteins contain five regions; PH, TH, SH3, SH2 and kinase domains. Mutations causing XLA may affect any of these domains. About 380 unique mutations have been identified and are collected in a mutation database, BTKbase. Here, we describe the structure, function, and interactions of the affected signaling molecules in atomic detail.

X-linked agammaglobulinemia

10.2741/vihinen

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Citations (53)

Newly diagnosed X-linked agammaglobulinemia (XLA), bruton's tyrosine kinase (Btk) mutation, in a 39 year-old male

Journal of Allergy and Clinical Immunology (2002)

Sean R Bulley J Zhang Suzanna Kwong Chaim M. Roifman

X-linked agammaglobulinemia

10.1016/s0091-6749(02)81694-3

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Citations (4)

Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction.

Proceedings of the National Academy of Sciences (1994)

Genhong Cheng Z S Ye David Baltimore

Bruton's tyrosine kinase (Btk) is a recently described B-cell-specific tyrosine kinase. Mutations in this gene lead to human X chromosome-linked agammaglobulinemia and murine X-linked immunodeficiency. Although genetic evidence strongly suggests that Btk plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remains unknown, primarily because the proteins that it interacts with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-aa motifs in Btk. An analogous site with the same specificity is also present in Itk, the T-cell-specific homologue of Btk. Our data extend the range of interactions mediated by Src homology 3 domains and provide an indication of a link between Btk and established signaling pathways in B lymphocytes.

LYN

FYN

Src family kinase

Tyrosine-protein kinase CSK

X-linked agammaglobulinemia

Protein kinase domain

10.1073/pnas.91.17.8152

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Citations (173)

Deficient Expression of Bruton's Tyrosine Kinase in Monocytes From X-Linked Agammaglobulinemia as Evaluated by a Flow Cytometric Analysis and Its Clinical Application to Carrier Detection

Blood (1998)

Takeshi Futatani Toshio Miyawaki Satoshi Tsukada S. Hashimoto Toshio Kunikata