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

Hum Mol Genet. 2005 Apr 1;14(7):885-92. doi: 10.1093/hmg/ddi081. Epub 2005 Feb 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromosomes, Human, Pair 22
  • DiGeorge Syndrome / genetics*
  • Disease Models, Animal
  • Frameshift Mutation
  • Gene Deletion
  • Genes, Reporter
  • Genome
  • Humans
  • Immunohistochemistry
  • Luciferases / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Mutation, Missense
  • Nuclear Localization Signals*
  • Phenotype
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • T-Box Domain Proteins / genetics*
  • Transcriptional Activation


  • Nuclear Localization Signals
  • T-Box Domain Proteins
  • TBX1 protein, human
  • Luciferases