title: A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient.
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.
authors.affiliation: Department of Pediatric Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Satoru
authors.initials: S
authors.lastname: Kumaki
authors.forename: Toru
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.forename: Chung
authors.initials: C
authors.lastname: Yeng Looi
authors.forename: Shin
authors.initials: S
authors.lastname: Kawai
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Minegishi
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sasahara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics; D002522:Chlorocebus aethiops; D018387:Codon, Initiator / Q000235:genetics*; D003598:Cytoskeletal Proteins; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics*; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D018387:Codon, Initiator; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C109903:WIPF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein