title: Somatic mosaicism in the Wiskott-Aldrich syndrome: molecular and functional characterization of genotypic revertants.
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.
authors.affiliation: Centre for Stem Cell Research, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA. brian.r.davis@uth.tmc.edu
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davis
authors.forename: Qing
authors.initials: Q
authors.lastname: Yan
authors.forename: Jacquelin H
authors.initials: JH
authors.lastname: Bui
authors.forename: Kumar
authors.initials: K
authors.lastname: Felix
authors.forename: Daniele
authors.initials: D
authors.lastname: Moratto
authors.forename: Linda M
authors.initials: LM
authors.lastname: Muul
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Prokopishyn
authors.forename: R Michael
authors.initials: RM
authors.lastname: Blaese
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D002999:Clone Cells; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009030:Mosaicism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics* / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D051316:Wiskott-Aldrich Syndrome Protein