Expression of the Gene Defect in X-Linked Agammaglobulinemia

Conley, Mary Ellen; Brown, Persymphonie; Pickard, Allan R.; Buckley, Rebecca H.; Miller, Debra S.; Raskind, Wendy H.; Singer, Jack W.; Fialkow, Philip J.

doi:10.1056/nejm198608283150907

Cited by 157 publications

(61 citation statements)

References 20 publications

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“…Despite current comprehensive care, studies in genetically defined XLA patients indicate that infectious and noninfectious morbidity remains high, with survival rates as low as 50% by age 45 29,30 (A. Plebani, Università di Brescia, oral communication at the XIIth Meeting of the European Society for Immunodeficiencies, October [4][5][6][7]2006). Although prospective studies [31][32][33] indicate that the overall prognosis in XLA is improved after earlier recognition and consistent immunoglobulin replacement and antibiotic therapy, these measures remain incompletely protective.…”

Section: Discussionmentioning

confidence: 99%

“…XLA carrier females and female Btk ϩ/Ϫ mice exhibit nonrandom X-inactivation in both bone marrow (BM) and peripheral B-lineage populations. 4,5 Transplantation of normal BM or fetal liver cells can rescue immune responses in XID mice without marrow conditioning. 6,7 Serum immunoglobulin levels and T-independent type 2 (TI-II) immune responses can be restored in sublethally irradiated animals with as few as 2.5 ϫ 10 4 donor cells and reconstitution of less than 10% WT cells in the spleen.…”

Section: Introductionmentioning

confidence: 99%

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B cell–specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia

Kerns

Ryu

Stirling

et al. 2010

Blood

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

B cell–specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia

Kerns

Ryu

Stirling

et al. 2010

Blood

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“…The defect in XLA and xid is intrinsic to the B cell, as heterozygous females manifest a unilateral X chromosome inactivation in the mature B cell populations (13,(21)(22)(23), due to a selective disadvantage of cells that have the defective Btk gene on the active X chromosome. Btk is expressed throughout B cell differentiation, except in plasma cells (8,13,24).…”

mentioning

confidence: 99%

Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region

Drabek

Raguz

Wit

et al. 1997

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

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Bruton tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase that is essential for B cell development. The Btk gene encodes a 659-amino acid protein that contains a single catalytic domain, the src homology domains SH2 and SH3, and a unique N-terminal region with a pleckstrin homology domain and proline-rich sequences (1, 2). Btk belongs to the Tec subfamily of tyrosine kinases, together with the homologous

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“…The causative defect seems to prevent transition of pre-B cells into B cells. Female obligate carriers of XLA appear to be immunologically normal, but X chromosome inactivation is not random in B lymphocytes, probably because the B cell in which the XLA-bearing chromosome is active cannot mature [5][6][7]. This feature enables female carriers to be identified in affected families [5].…”

Section: Introductionmentioning

confidence: 99%

An exon‐skipping mutation in thebtk gene of a patient with X‐linked agammaglobulinemia and isolated growth hormone deficiency

et al. 1994

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X-linked agammagiobulinemia (XLA) is an inherited immunodeficiency disease associated with a block in differentiation from pre-B to B cells. The XLA gene encodes a 659 amino acids cytoplasmic protein tyrosine kinase named btk (Bruton's tyrosine kinase). The few btk gene alterations so far reported in XLA patients are heterogenous and distributed in all domains of the btk protein. They appear to be responsible for a range of B call immunodeficieney disorders of variable severity. Rare families in which XLA is inherited together with isolated growth hormone deficiency (IGHD) have been reported. Genetic analysis has shown that this disease association maps to the same region of the X chromosome as XLA, but whether the two phenotypes are caused by a common or different developmental or biochemical mechanism is unknown. We have analysed the btk gene of a patient with XLA and IGHD. RT-PCR analysis of btk transcripts, sequencing data obtained from eDNA and genomic DNA and in vitro splicing assays showed that an intronic point mutation (1882 + 5G--->A) is responsible for skipping of an exon located in the tyrosine kinase domain. This exon-skipping event results in a frameshift leading to a premature stop codon 14 amino acids downstream, and in the loss of the last 61 residues of the earboxy-terminal end of the protein. Although we studied a sporadic case, the results suggest that an alteration of the btk gene might cause this unusual phenotype.

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Expression of the Gene Defect in X-Linked Agammaglobulinemia

Cited by 157 publications

References 20 publications

B cell–specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia

B cell–specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia

Correction of the X-linked immunodeficiency phenotype by transgenic expression of human Bruton tyrosine kinase under the control of the class II major histocompatibility complex Ea locus control region

An exon‐skipping mutation in thebtk gene of a patient with X‐linked agammaglobulinemia and isolated growth hormone deficiency

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