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 TH 1 -differentiation . Hot-spot WAS mutations Thr 45 Met and Arg 86 C ys , which result in XLT-to -WAS disease progression , impair recruitment of hBRM- but not BRG 1 -enriched BAF-complexes to IFNG and TBX 21 promoters . Moreover , promoter-enrichment of histone H 2 A .Z and its catalyzing enzyme EP 400 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 TH 1 -genes . In contrast , patient-mutations Ala 236 Gly and Arg 477 Lys that manifest in XLT without progressing to WAS do not disrupt chromatin-remodeling or transcriptional-reprogramming of TH 1 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
Validation

Diseases presenting "thrombocytopenia" symptom

22q11.2 deletion syndrome

adrenomyeloneuropathy

dedifferentiated liposarcoma

erythropoietic protoporphyria

esophageal adenocarcinoma

heparin-induced thrombocytopenia

hodgkin lymphoma, classical

holt-oram syndrome

homocystinuria without methylmalonic aciduria

liposarcoma

malignant atrophic papulosis

monosomy 21

oculocutaneous albinism

scrub typhus

sneddon syndrome

typhoid

waldenström macroglobulinemia

wiskott-aldrich syndrome

This symptom has already been validated