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Human Molecular Genetics Advance Access originally published online on February 9, 2005
Human Molecular Genetics 2005 14(7):885-892; doi:10.1093/hmg/ddi081
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation

Jason Z. Stoller1,2 and Jonathan A. Epstein2,*

1Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA and 2Cardiovascular Division, Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA 19104, USA

* To whom correspondence should be addressed at: 954 BRB II, 421 Curie Boulevard, Philadelphia, PA 19104, USA. Tel: +1 2158988731; Fax: +1 2155739306; Email: epsteinj{at}mail.med.upenn.edu

Received December 14, 2004; Accepted February 1, 2005

DiGeorge syndrome (DGS) is the most common human chromosomal deletion syndrome and is frequently associated with deletions on chromosome 22q11. Approximately 17% of patients with the phenotypic features of this syndrome have no detectable genomic deletion. Animal studies using mouse models have implicated Tbx1 as a critical gene within the commonly deleted region, and several mutations in TBX1 have been identified recently in non-deleted patients, including missense and frameshift mutations. The mechanisms by which these mutations cause disease have remained unclear. We have identified a previously unrecognized and novel nuclear localization signal (NLS) at the C-terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in these patients. This NLS is conserved across species, among a subfamily of T-box proteins including Brachyury and Tbx10, and among additional nuclear proteins. By providing functional data to indicate loss-of-function produced by the 1223delC TBX1 mutation, our results provide strong support for the conclusion that TBX1 mutations can cause DGS in humans.


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