Background The Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations in WAS , which encodes for WAS protein (WASP). The WASP-interacting protein (WIP) stabilizes ...WASP, as evidenced by severely decreased WASP levels in T cells from WIP-deficient mice. The majority of missense mutations in patients with WAS/XLT are located in the WIP-binding domain of WASP and might result in dissociation of the WASP-WIP complex and WASP degradation. Objective To restore WASP levels and correct T-cell function in WAS/XLT patients with mutations in the WIP-binding domain of WASP. Methods WIP, and a WIP-derived 41–amino acid–long peptide, which interacts with WASP and was designated nanoWIP (nWIP), were fused to enhanced green fluorescent protein and introduced by electroporation into EBV-transformed B cells, and by retroviral transduction into purified blood T cells from patients with WAS. WASP levels were measured by intracellular fluorescence-activated cell sorting staining. The actin cytoskeleton was visualized by intracellular phalloidin staining. Results Introduction of WIP and nWIP restored WASP levels to normal in EBV-transformed B-cell lines from XLT patients with missense mutations in the WIP-binding domain of WASP and residual WASP levels, and corrected the defective spreading and pseudopodia formation of their T cells in response to immobilized anti-CD3. Conclusion A WASP-binding WIP-derived peptide stabilizes WASP in cells from XLT patients with missense mutations that disrupt WIP binding, and corrects their T-cell actin cytoskeleton defect. This may provide a novel therapeutic strategy for these patients.
Background Cartilage hair hypoplasia is an autosomal recessive type of metaphyseal chondrodysplasia, caused by mutations in the ribonuclease mitochondrial RNA processing ( RMRP ) gene. Typical ...features of cartilage hair hypoplasia include short stature, a predisposition to malignancy, and a variable degree of impairment of cellular immunity. Objective We sought to describe the heterogeneity of clinical and immunologic phenotype in 12 consecutive patients with RMRP mutations who were referred to 2 different institutions for immunologic evaluation. Methods We have retrospectively analyzed the clinical and laboratory features in 12 patients with molecular defects in the RMRP gene. T-cell repertoire was investigated by quantitating Vβ families' expression and analyzing their diversity. T-cell receptor excision circle analysis was used to study thymic output. Results All 12 patients had significant immune abnormalities, leading to severe immune deficiency in 9. CD8 lymphocytopenia was identified as a novel phenotype associated with RMRP mutations. Significant, even intrafamilial, phenotypic heterogeneity was observed. In 3 cases, severe immunodeficiency was the only phenotypic manifestation associated with RMRP mutations, a novel finding. Mutations leading to significant immune defects were most often located in the promoter, and the first case of a compound heterozygote for 2 such mutations is reported. Conclusion This report broadens the spectrum of phenotypes associated with RMRP mutations and suggests that mutations in this gene should be considered when evaluating patients with combined immune deficiency, regardless of the presence of other manifestations.
We report a case of Omenn Syndrome presenting in association with aniridia arising from 3 maternally-inherited RAG mutations compounded by a deletion encompassing
RAG
and
PAX6
genes on the ...paternally-inherited chromosome.
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