A Point Mutation in the SH2 Domain of Bruton's Tyrosine Kinase in Atypical X-Linked Agammaglobulinemia

Saffran, Douglas C.; Parolini, Ornella; Fitch-Hilgenberg, M.E.; Rawlings, David J.; Afar, Daniel; Witte, Owen N.; Conley, Mary Ellen

doi:10.1056/nejm199405263302104

Cited by 122 publications

(49 citation statements)

References 20 publications

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“…Our results suggest that R335W mutant ITK causes a profound instability of the ITK protein rather than an impairment of ITK activation. Interestingly, mutations at exactly analogous positions within the SH2 domain have been described in BTK (Y361C) (17) and SAP (Q99P) (18), both leading to protein instability and the clinical phenotype of atypical X-linked agammaglobulinemia (XLA) and XLP, respectively ( Figure 3D). …”

Section: Discussionmentioning

confidence: 61%

Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation

Huck¹,

Feyen²,

Niehues³

et al. 2009

J. Clin. Invest.

265

207

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The fatal immune dysregulation that sometimes follows EBV infection in boys has been linked to mutations in two X chromosome-encoded genes, SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis (XIAP). In this study we describe 2 girls from a consanguineous Turkish family who died after developing severe immune dysregulation and therapy-resistant EBV-positive B cell proliferation following EBV infection. SNP array-based genome-wide linkage analysis revealed IL-2-inducible T cell kinase (ITK) as a candidate gene for this immunodeficiency syndrome. Both girls harbored a homozygous missense mutation that led to substitution of a highly conserved residue (R335W) in the SH2 domain of ITK. Characteristics of ITK deficiency in mouse models, such as absence of NKT cells and high levels of eomesodermin in CD8 + cells, were seen in either one or both of the girls. Two lines of evidence suggested that R335W caused instability of the ITK protein. First, in silico modeling of the mutant protein predicted destabilization of the SH2 domain. Additionally, Western blot analysis revealed that, unlike wild-type ITK, the R335W mutant was nearly undetectable when expressed in 293 T cells. Our results suggest that ITK deficiency causes what we believe to be a novel immunodeficiency syndrome that leads to a fatal inadequate immune response to EBV. Because ITK deficiency resembles EBV-associated lymphoproliferative disorders in boys, we suggest that this molecular cause should be considered during diagnosis and treatment.

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Section: Discussionmentioning

confidence: 61%

Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation

Huck¹,

Feyen²,

Niehues³

et al. 2009

J. Clin. Invest.

265

207

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“…(7) Finally, the milder disease phenotype in patients with partial Btk activity suggests that even limited restoration of enzymatic activity may provide clinical benefit. 38,39 Several observations, however, merit additional attention before proceeding toward clinical application in XLA:…”

Section: Discussionmentioning

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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“…An SH2 mutant of Btk cannot rescue signaling defects in a Btk de®cient chicken B cell line (Takata et al, 1996), and the capacity of Btk to maintain a sustained increase in intracellular calcium is SH2 dependent (Zuomei Li et al, manuscript in preparation). In addition, mutations in the SH2 domain have been identi®ed in XLA patients (Sa ran et al, 1994;Ochs HD and Smith CI, 1996). The R307K mutation does not prevent Btk* transformation of NIH3T3 cells, however (Li et al, 1995).…”

Section: The Sh2 Domain Plays a Critical Role In Btk Signalingmentioning

confidence: 99%

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

Rawlings

Park

et al. 1997

Oncogene

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Mutations in the nonreceptor tyrosine kinase Btk result in the B cell immunode®ciencies X-linked agammaglobulinemia (XLA) in humans and X-linked immunode®-ciency (xid) in mice. Genetic and biochemical evidence implicates Btk as a key component of several B cell signaling pathways. Activation of Btk by a point mutation (E41K) within the PH domain (Btk*) results in ®broblast transformation and is correlated with increased membrane localization of Btk. When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction. To determine whether membrane association is su cient to activate Btk, we targeted Btk to the plasma membrane using a series of fusion proteins including GagBtk, CD16Btk and CD4Btk. Constitutive membrane association greatly enhanced the ability of Btk to transform Rat2 ®broblasts in the presence of high levels of Src activity. All membrane targeted forms of Btk were highly tyrosine phosphorylated. Transformation required membrane localization, Btk kinase activity, transphosphorylation by Src family kinases, and an intact SH2 domain but not the PH or SH3 domains. These data suggest that membrane localization is a critical early step in Btk activation.

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A Point Mutation in the SH2 Domain of Bruton's Tyrosine Kinase in Atypical X-Linked Agammaglobulinemia

Cited by 122 publications

References 20 publications

Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation

Girls homozygous for an IL-2–inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation

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

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

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