Rare Diseases Symptoms Automatic Extraction

Disruption of hSWI/SNF-Complexes in T cells by WAS Mutations Distinguishes X-linked Thrombocytopenia from Wiskott-Aldrich Syndrome.

[wiskott-aldrich syndrome]

Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder, and X-linked thrombocytopenia (XLT), a bleeding disorder, both arise from nonsynonymous mutations in WAS, which encodes a hematopoietic-specific WASp. Intriguingly, XLT evolves into WAS in some patients but not in others, yet the biological basis for this cross-phenotype (CP) effect remains unclear. Using human T helper (TH) cells expressing different disease-causing WAS mutations, we demonstrate that hSWI/SNF-like complexes require nuclear-WASp to execute their chromatin-remodeling activity at promoters of WASp-target, immune function genes during TH1-differentiation. Hot-spot WAS mutations Thr45Met and Arg86Cys, which result in XLT-to-WAS disease progression, impair recruitment of hBRM- but not BRG1-enriched BAF-complexes to IFNG and TBX21 promoters. Moreover, promoter-enrichment of histone H2A.Z and its catalyzing enzyme EP400 are both impaired. Consequently, activation of Notch signaling, a hBRM-regulated event, and its downstream effector NF-κB are both compromised, along with decreased accessibility of nucleosomal-DNA and inefficient transcription-elongation of WASp-target TH1-genes. In contrast, patient-mutations Ala236Gly and Arg477Lys that manifest in XLT without progressing to WAS do not disrupt chromatin-remodeling or transcriptional-reprogramming of TH1 genes. Our study defines an indispensible relationship between nuclear-WASp and hSWI/SNF-complexes in gene activation, and reveals molecular distinctions in TH cells that might contribute to disease severity in the XLT/WAS clinical spectrum.

Diseases presenting "immunodeficiency" symptom

  • adrenal incidentaloma
  • allergic bronchopulmonary aspergillosis
  • cushing syndrome
  • dracunculiasis
  • hirschsprung disease
  • hodgkin lymphoma, classical
  • homocystinuria without methylmalonic aciduria
  • kabuki syndrome
  • legionellosis
  • malignant atrophic papulosis
  • oculocutaneous albinism
  • omenn syndrome
  • papillon-lefèvre syndrome
  • primary effusion lymphoma
  • primary hyperoxaluria type 1
  • pyomyositis
  • severe combined immunodeficiency
  • sneddon syndrome
  • werner syndrome
  • wiskott-aldrich syndrome
  • wolf-hirschhorn syndrome
  • x-linked adrenoleukodystrophy

This symptom has already been validated