title: Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation.
abstract: 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.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Stoller
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22; D004062:DiGeorge Syndrome / Q000235:genetics*; D004195:Disease Models, Animal; D016368:Frameshift Mutation; D017353:Gene Deletion; D017930:Genes, Reporter; D016678:Genome; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D019913:Nuclear Localization Signals; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D020825:T-Box Domain Proteins / Q000235:genetics*; D015533:Transcriptional Activation
chemical_list: D019913:Nuclear Localization Signals; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; D008156:Luciferases