A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient

Human Mutation
Wei DuShigeru Tsuchiya

Abstract

Wiskott-Aldrich syndrome (WAS) is caused by mutations in the gene encoding WAS protein (WASP ). Recently, somatic mosaicism caused by reversions or second-site mutations has been reported in some inherited disorders including WAS. In this article, we describe somatic mosaicism in a 15-year-old WAS patient due to a second-hit mutation in the initiation codon. The patient originally had a single-base deletion (c.11delG; p.G4fsX40) in the WAS (WASP) gene, which resulted in a frameshift and abrogated protein expression. Subsequently, a fraction of T and natural killer (NK) cells expressed a smaller WASP, which binds to its cellular partner WASP-interacting protein (WIP). The T and NK cells were found to have an additional mutation in the initiation codon (c.1A>T; p.M1_P5del). The results strongly suggest that the smaller WASP is translated from the second ATG downstream of the original mutation, and not only T cells but also NK cells carrying the second mutation acquired a growth advantage over WASP negative counterparts. To our knowledge, this is the first report describing somatic mosaicism due to a second-site mutation in the initiation codon of any inherited disorders.

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Citations

Jan 9, 2009·Immunologic Research·Brian R Davis, Fabio Candotti
Jul 28, 2012·International Journal of Molecular Sciences·Elad NoyMira Barda-Saad
Sep 4, 2015·Pediatrics International : Official Journal of the Japan Pediatric Society·Yoji Sasahara
Aug 1, 2009·Hematological Oncology·Ranran ZhangThomas P Loughran
Nov 4, 2008·Current Opinion in Allergy and Clinical Immunology·Taizo Wada, Fabio Candotti
Feb 18, 2010·The Journal of Allergy and Clinical Immunology·Sara TrifariLoïc Dupré
May 21, 2013·The Journal of Allergy and Clinical Immunology·Yuko WatanabeShigeru Tsuchiya
Jan 5, 2011·Trends in Molecular Medicine·Joey E Lai-CheongJouni Uitto

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