Mutation Screening of the BTK Gene in 56 Families With X-Linked Agammaglobulinemia (XLA): 47 Unique Mutations Without Correlation to Clinical Course

Holinski‐Feder, Elke; Weiss, Michael; Brandau, Oliver; Jedele, KB; Nore, Beston F.; Backesjo, CM; Vihinen, Mauno; Hubbard, SR; Bh, Belohradsky; Smith, C. I. Edvard; Meindl, Alfons

doi:10.1542/peds.101.2.276

Cited by 110 publications

(89 citation statements)

References 34 publications

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“…6). From in vitro kinase assays of BTK mutants derived from BTK-deficient X-linked agammaglobulinemia patients, it is known that truncation of the BTK kinase domain at amino acid 520 and even replacement mutations in the distal portion of the kinase domain result in a complete loss of BTK kinase activity (4). Hence, only full-length BTK but none of the truncated BTK splice variants identified here should exhibit BTK kinase activity (Table 1, Fig.…”

Section: Rare Occurrence Of Somatic Mutations Of the Btk Gene In B Cellmentioning

confidence: 89%

“…BTK kinase deficiency in humans leading to X-linked agammaglobulinemia results in a breakdown of pre-B cell receptor signals and a differentiation block at the pre-B cell stage (4). In normal pre-B cells, engagement of the pre-B cell receptor using a -chainspecific antibody (arrows, Fig.…”

Section: Expression Of Kinase-deficient Btk Prevents Pre-b Cell Recepmentioning

confidence: 99%

“…Pre-B lymphoblastic leukemia cells typically exhibit a differentiation block at the pre-B cell stage of development (2); likewise, BTK deficiency in humans leading to X-linked agammaglobulinemia results in a breakdown of pre-B cell receptor signals and a differentiation block at the pre-B cell stage (4). To elucidate a possible role for BTK in leukemic transformation of human B cell precursors, we investigated BTK function in pre-B acute lymphoblastic leukemia cells.…”

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confidence: 99%

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Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells

Feldhahn

Rı́o

Soh

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Bruton's tyrosine kinase (BTK) deficiency results in a differentiationpre-B cell receptor ͉ differentiation block ͉ apoptosis R ecent findings by us and others (1, 2) suggested a role for the pre-B cell receptor and related signaling molecules as a tumor suppressor to prevent the development or limit the proliferation of leukemic cells. BCR-ABL1 ϩ pre-B lymphoblastic leukemia cells frequently exhibit defective expression of the pre-B cell receptor related signaling molecule SLP65 (1) and acquire independence from pre-B cell receptor-dependent survival signals (2). The analysis of mouse mutants of the pre-B cell receptor-related signaling molecules SLP65 and Bruton's tyrosine kinase (BTK) demonstrated that SLP65 and BTK cooperate to suppress leukemic transformation (3).Pre-B lymphoblastic leukemia cells typically exhibit a differentiation block at the pre-B cell stage of development (2); likewise, BTK deficiency in humans leading to X-linked agammaglobulinemia results in a breakdown of pre-B cell receptor signals and a differentiation block at the pre-B cell stage (4). To elucidate a possible role for BTK in leukemic transformation of human B cell precursors, we investigated BTK function in pre-B acute lymphoblastic leukemia cells. Materials and MethodsPatient Samples, Cell Lines, and Cell Purification. Normal CD19 ϩ -chain Ϫ pro-B cells and CD19 ϩ VpreB ϩ pre-B cells were sorted from human bone marrow from four healthy donors (purchased from Cambrex, Baltimore) by using immunomagnetic beads against CD19 (Miltenyi Biotech, Bergisch Gladbach, Germany) and cell sorting using antibodies against CD19, VpreB (BD Biosciences, Heidelberg, Germany), and the -chain (Jackson ImmunoResearch). Similarly, CD5 ϩ CD19 ϩ B1 cells, IgD ϩ CD27 Ϫ naïve B cells, CD19 ϩ CD27 ϩ memory B cells, and CD19 ϩ CD138 ϩ plasma cells were sorted from peripheral blood of four healthy donors by using antibodies against CD5, CD19, CD27, CD138, and IgD (BD Biosciences).In total, 29 B cell precursor leukemias including 12 cell lines and 17 primary cases were studied. Eleven cases of B cell precursor leukemia with MLL-AF4 gene rearrangement [t (4, 11)(q21;q23)] including eight primary cases (I-VIII, Table 1, which is published as supporting information on the PNAS web site) and three cell lines (BEL1, RS4;11, and SEM) were analyzed. Eleven samples carrying a BCR-ABL1 gene rearrangement [t (9, 22)(q34;q11)] including seven primary cases (IX-XV, Table 1) and four cell lines (BV173, Nalm1, SD1, and SUP-B15) were studied. In addition, three leukemia cell lines carrying an E2A-PBX1 gene rearrangement [t (1, 19) (q23;p13); 697, Kasumi2, and MHH-CALL3], three cases of pre-B lymphoblastic leukemia with TEL-AML1 fusion gene [t (12, 21)(p12;q22)] including two primary cases (XVIII and XIX, Table 1), and the cell line REH and one pre-B lymphoblastic leukemia cell line harboring a TEL-PDGFRB gene rearrangement [Nalm6; t (5, 12)(q33.2;p13.2)] were studied. For all cases, fusion transcripts resulting from oncogenic gene rearrangements were detected by PCR as desc...

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Section: Rare Occurrence Of Somatic Mutations Of the Btk Gene In B Cellmentioning

confidence: 89%

Section: Expression Of Kinase-deficient Btk Prevents Pre-b Cell Recepmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells

Feldhahn

Rı́o

Soh

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…We have predicted the consequences of all the mutations on protein structure and function based on sequence and structure information [Holinski-Feder et al, 1998;Jin et al, 1995;Korpi et al, 2000;Maniar et al, 1995;Mattsson et al, 2000;Okoh and Vihinen, 1999;Saha et al, 1997;Shen and Vihinen, 2004;Speletas et al, 2001;Vihinen et al, 1995aVihinen et al, ,b, 1994aVoøchovský et al, 1995;Zhu et al, 1994]. In Figure 6, all the disease causing missense mutations are indicated within PH, SH2, and the kinase domains.…”

Section: Structure^function Correlationsmentioning

confidence: 99%

BTKbase: the mutation database for X-linked agammaglobulinemia

Väliaho¹,

Smith²,

Vihinen³

2006

Hum. Mutat.

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185

139

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For the Immunogenetics Special IssueX-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). XLA patients have a decreased number of mature B cells and a lack of all immunoglobulin isotypes, resulting in susceptibility to severe bacterial infections. XLA-causing mutations are collected in a mutation database (BTKbase), which is available at http://bioinf.uta.fi/BTKbase. For each patient the following information is given (when available): the identification of the entry, a plain English description of the mutation followed by a reference, formal characterization of the mutation, and the various parameters from the patient. BTKbase is implemented with the MUTbase program suite, which provides an easy, interactive, and quality controlled submission of information to mutation databases.

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“…Thus, it is not surprising that the known single codon hot spot R520 (Hagemann et al, 1994;Zhu et al, 1994;Conley et al, 1994;Gaspar et al, 1995) was found in our study cohort, in three independent families (families 19-21) with two different missense mutations (R520G and R520Q) ( Table 1). Other arginine-coding CpG dinucleotide was implicated in the recurrent substitution R562W (patient 26), located close to the catalytic site of the protein and interacting with the side chain of the invariant W563 (Hagemann et al, 1994;Conley et al, 1994;Vorechovsky et al, 1995;Holinski-Feder et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

Bruton tyrosine kinase gene mutations in Argentina

et al. 2003

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The block in differentiation from pro-B to pre-B cells results in a selective defect in the humoral immune response characteristic of human X-linked agammaglobulinemia (XLA). Mutations of Bruton tyrosine kinase (BTK) gene have been identified as the cause of XLA. Mutation detection is the most reliable method for making a definitive diagnosis, except when clinical and laboratory findings are distinctive and coupled with history of X-linked inheritance. To provide a definitive diagnosis to 40 families incorporated in the Argentinian Primary Immunodeficiencies Registry we analysed the BTK gene by SSCP analysis as screening method for XLA, followed by direct sequencing. The molecular defect was localized in 45 patients from 34 unrelated families. From the 34 independent mutations identified, 16 were previously undescribed, 31 were unique mutations, 22 were exonic single nucleotide changes (16 missense and 6 nonsense) and four intronic mutations. Because five families had clinical, immunological and inheritance data sufficient for a definitive diagnosis, our study allowed 37 patients from 29 families previously categorized probable/ possible XLA, have now definitive diagnosis leading to appropriate genetic counseling.

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Mutation Screening of the BTK Gene in 56 Families With X-Linked Agammaglobulinemia (XLA): 47 Unique Mutations Without Correlation to Clinical Course

Cited by 110 publications

References 34 publications

Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells

Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells

BTKbase: the mutation database for X-linked agammaglobulinemia

Bruton tyrosine kinase gene mutations in Argentina

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