Somatic mosaicism in the Wiskott-Aldrich syndrome: molecular and functional characterization of genotypic revertants.

Clinical Immunology : the Official Journal of the Clinical Immunology Society
Brian R DavisFabio Candotti

Abstract

The reasons underlying the occurrence of multiple revertant genotypes in Wiskott-Aldrich syndrome (WAS) patients remain unclear. We have identified more than 30 revertant genotypes in a C995T WAS patient having 10-15% revertant, WAS protein (WASp)-expressing circulating lymphocytes. Of 497 allospecific T-cell clones generated from the peripheral blood, 47.1% carried a revertant sequence. All revertant T-cell clones exhibited restoration of WASp expression. However, anti-CD3-induced proliferative responses varied greatly amongst revertants. Several revertant T-cell clones expressed an internally deleted WASp mutant lacking much of the proline-rich region. This potentially accounts for the reduced anti-CD3 proliferative responses of these T-cell clones. We found no evidence for an increased DNA mutation rate in this patient. We conclude that the diversity of revertant genotypes in our patient does not result from an extraordinary mutation rate and that the amino acid sequence space explored by WASp in revertant T-cells is significantly smaller than might have been predicted from the diversity of revertant genotypes.

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Citations

Apr 9, 2011·Nature Medicine·Mike May
Oct 12, 2010·Science·Brian R Davis, Fabio Candotti
Jul 15, 2015·Expert Review of Clinical Immunology·Austen J J Worth, Adrian J Thrasher
Jan 5, 2011·Trends in Molecular Medicine·Joey E Lai-CheongJouni Uitto
Feb 10, 2012·The Journal of Investigative Dermatology·Anna M G PasmooijMarcel F Jonkman
Oct 21, 2015·Molecular Genetics and Genomics : MGG·Marzena Gajecka
Jun 11, 2017·Blood·Jonathan M Marron, Steven Joffe
Feb 26, 2016·Clinical and Vaccine Immunology : CVI·Roshini S Abraham, Geraldine Aubert
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Nov 10, 2020·Biochimie·Mauno Vihinen
Apr 18, 2021·Journal of Clinical Immunology·Jahnavi Aluri, Megan A Cooper
Jul 15, 2021·British Journal of Haematology·Andrew D Hughes, Peter Kurre

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