Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

フォーマット:

論文

責任表示:

Wada, Taizo ; Konno, Akihiro ; Schurman, Shepherd H. ; Garabedian, Elizabeth K. ; Anderson, Stacie M. ; Kirby, Martha ; Nelson, David L. ; Candotti, Fabio

言語:

英語

出版情報:

American Society for Clinical Investigation, 2003-05-01

著者名:

Wada, Taizo

Konno, Akihiro

Schurman, Shepherd H.

Garabedian, Elizabeth K.

Anderson, Stacie M.

Kirby, Martha

Nelson, David L.

Candotti, Fabio

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掲載情報:

Journal of Clinical Investigation

ISSN:

0021-9738      

巻:

111

通号:

9

開始ページ:

1389

終了ページ:

1397

バージョン:

publisher

概要:

金沢大学附属病院小児科<br />Revertant mosaicism due to true back mutations or second-site mutations has been identified in several inherited disorders. The occurrence of revertants is considered rare, and the underlying genetic mechanisms remain … mostly unknown. Here we describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS). The original mutation causing disease in this family is a single base insertion (1305insG) in the WAS protein (WASP) gene, which results in frameshift and abrogates protein expression. Both patients, however, showed expression of WASP in a fraction of their T cells that were demonstrated to carry a second-site mutation causing the deletion of 19 nucleotides from nucleotide 1299 to 1316. This deletion abrogated the effects of the original mutation and restored the WASP reading frame. In vitro expression studies indicated that mutant protein encoded by the second-site mutation was expressed and functional, since it was able to bind to cellular partners and mediate T cell receptor/CD3 downregulation. These observations were consistent with evidence of in vivo selective advantage of WASP-expressing lymphocytes. Molecular analysis revealed that the sequence surrounding the deletion contained two 4-bp direct repeats and that a hairpin structure could be formed by five GC pairs within the deleted fragment. These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients. 続きを見る

URL:

http://hdl.handle.net/2297/20621