Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome.
Rare cases of somatic mosaicism resulting from reversion of inherited mutations can lead to the attenuation of blood-cell disorders, including Wiskott-Aldrich syndrome (WAS). The impact of the revertant hematopoietic stem or progenitor cells, particularly their representation in blood-cell populations, is of interest because it predicts the outcome of gene therapy. Here we report an 8-year-old patient with WAS caused by a single nucleotide insertion in the WASP gene that abrogates protein expression. The patient nonetheless had mild disease. We found reversion of the mutation in a fraction of patient lymphocytes. Forty percent of natural killer (NK) cells expressed Wiskott-Aldrich syndrome protein (WASP), and NK cells contained both mutated and revertant (normal) sequences. WASP was not expressed in patient T or B cells; T cells contained only the mutated sequence. The selective advantage of WASP+ NK cells was also demonstrated for carrier females. The enrichment of WASP+-revertant NK cells indicates that WASP provides a selective advantage in this lineage and predicts the success of gene therapy for reconstituting the NK-cell compartment. The importance of reconstituting the NK-cell lineage is discussed.
Lutskiy
Maxim I
MI
The CBR Institute for Biomedical Research, Inc., Boston, MA 02115, USA.
Beardsley
Diana S
DS
Rosen
Fred S
FS
Remold-O'Donnell
Eileen
E
D001483:Base Sequence; D002648:Child; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D009030:Mosaicism; D009154:Mutation / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology*; D051316:Wiskott-Aldrich Syndrome Protein
D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein