ArticleThe Journal of clinical investigation2003
Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 84 citations in OpenAlex.
- Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.Science (New York, N.Y.) · 2013Trial
- Somatic mutations in autoinflammatory and autoimmune disease.Nature reviews. Rheumatology · 2024Review
- The Wiskott-Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation.Frontiers in immunology · 2023Article
- Identification of a novel WAS mutation and the non-splicing effect of a second-site mutation in a Chinese pedigree with Wiskott-Aldrich syndrome.Orphanet journal of rare diseases · 2022Article
- Lymphocytes Utilize Somatic Mutations, Epigenetic Silencing, and the Proteasome to Escape Truncated WASP Expression.Journal of clinical immunology · 2022Article
- Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome.Nature medicine · 2022Article
- Reversion Mosaicism in Primary Immunodeficiency Diseases.Frontiers in immunology · 2021Review
- Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells.The Journal of allergy and clinical immunology · 2020Article
- Somatic genetic rescue in Mendelian haematopoietic diseases.Nature reviews. Genetics · 2019Review
- T-cell defects in patients withBlood · 2018Article
- Human hyper-IgE syndrome: singular or plural?Mammalian genome : official journal of the International Mammalian Genome Society · 2018Review
- Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome.Journal of clinical immunology · 2018Review
- Gene Correction of iPSCs from a Wiskott-Aldrich Syndrome Patient Normalizes the Lymphoid Developmental and Functional Defects.Stem cell reports · 2016Article
- Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome.Frontiers in immunology · 2015Review
- Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.Clinical and experimental immunology · 2014Article
- Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases.International journal of hematology · 2014Review
- A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.Haematologica · 2013Article
- Expansion of somatically reverted memory CD8+ T cells in patients with X-linked lymphoproliferative disease caused by selective pressure from Epstein-Barr virus.The Journal of experimental medicine · 2012Article
- Revertant mosaicism in skin: natural gene therapy.Trends in molecular medicine · 2011Review
- WASP: a key immunological multitasker.Nature reviews. Immunology · 2010Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Revertant mosaicism due to true back mutations or second-site mutations has been identified in several inherited disorders. The occurrence of revertants is considered rare, and the underlying genetic mechanisms remain mostly unknown. Here we describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS). The original mutation causing disease in this family is a single base insertion (1305insG) in the WAS protein (WASP) gene, which results in frameshift and abrogates protein expression. Both patients, however, showed expression of WASP in a fraction of their T cells that were demonstrated to carry a second-site mutation causing the deletion of 19 nucleotides from nucleotide 1299 to 1316. This deletion abrogated the effects of the original mutation and restored the WASP reading frame. In vitro expression studies indicated that mutant protein encoded by the second-site mutation was expressed and functional, since it was able to bind to cellular partners and mediate T cell receptor/CD3 downregulation. These observations were consistent with evidence of in vivo selective advantage of WASP-expressing lymphocytes. Molecular analysis revealed that the sequence surrounding the deletion contained two 4-bp direct repeats and that a hairpin structure could be formed by five GC pairs within the deleted fragment. These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients.
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