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

Stoller, Jason Z.; Epstein, Jonathan A.

doi:10.1093/hmg/ddi081

Cited by 69 publications

(68 citation statements)

References 38 publications

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“…The 1232T4C nucleotide change is nine nucleotides downstream of a previously described frameshift mutation (1223delC) that eliminates a nuclear localisation signal and a transactivation domain essential for the TBX1 function. 18 The L411P change is not situated within the identified nuclear localisation signal but affects a residue conserved in all vertebrate species and that consequently seems to be essential for the correct TBX1 function.…”

Section: Resultsmentioning

confidence: 99%

Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

et al. 2007

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A screen for TBX1 gene mutations identified two mutations in patients with some features compatible with the 22q11.2-deletion syndrome but with no deletions. One is a de novo missense mutation and the other is a 5 0 untranslated region (5 0 UTR) C4T change that affects a nucleotide with a remarkable trans-species conservation. Computer modelling shows that the 5 0 UTR change is likely to affect the mRNA structure and in vitro translation experiments demonstrate that it produces a twofold increase in translation efficiency. Recently, duplications in the 22q11.2 region were reported in patients referred for fragile-X determination because of cognitive and behavioural problems. Because the 5 0 UTR nucleotide change may be a functional equivalent of a duplication of the TBX1 gene, we decided to screen 200 patients who had been referred for fragile-X determination and 400 healthy control individuals. As a result, we found the 5 0 UTR mutation to be present in three patients with mental retardation or behavioural problems and absent in control individuals of the same ethnic background. This observation suggests that it may be reasonable to screen for such mutation among patients with unspecific cognitive deficits and we provide an easy and quick way to do it with an amplification refractory mutation system (ARMS) approach. To our knowledge, this is the first human mutation showing that TBX1 is a candidate causing mental retardation associated with the 22q11.2 duplication syndrome.

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Section: Resultsmentioning

confidence: 99%

Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

et al. 2007

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“…For example, certain T-box family members have been found to possess nuclear localization signals (NLS), which may explain the shuttling of these proteins into the nucleus. In patients suffering from DiGeorge syndrome, the deletion of the NLS in Tbx1 has been shown to prevent the mutant protein from localizing to the nucleus, resulting in haploinsufficiency of the protein (49). Furthermore, deletion of the Tbx3 NLS, RREKRK, at amino acids 292-297 results in mislocalization of the protein to either perinuclear or cytoplasmic sites (9).…”

Section: Discussionmentioning

confidence: 99%

UV-mediated Regulation of the Anti-senescence Factor Tbx2

Abrahams

Mowla

Parker

et al. 2008

Journal of Biological Chemistry

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Several lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclindependent kinase inhibitors p19 ARF and p21 WAF1/CIP1/SDII. Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using sitedirected mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21 WAF1/CIP1/SDII promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2.

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“…The frameshift created by 1320-1342del23bp starts at codon 440 in the C terminus of the TBX1 protein and extends the protein from 504 to 616 amino acids. Although the mutation does not affect the T-box, it disrupts the central domain (amino acids 439-448) of a highly conserved nuclear localization signal (NLS) of the wild-type TBX1 protein (37), where it changes the conserved residues PYP to WPR (see Fig. 6, which is published as supporting information on the PNAS web site).…”

Section: Mutation Analysis In Patientsmentioning

confidence: 99%

Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome

Paylor

Glaser

Mupo³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

303

268

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About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1͞؉ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. Tbx1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral͞psychiatric phenotype. A likely role for Tbx1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbx1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.mouse model ͉ psychiatric disease ͉ DiGeorge syndrome ͉ sensorimotor gating C aused by a heterozygous multigene deletion, 22q11 deletion syndrome (22q11DS) is a relatively common genetic disorder (1:4,000 live births). Behavioral and psychiatric disorders are a prominent part of the 22q11DS phenotype. In children, these disorders include cognitive defects, anxiety, attention deficit disorder, and problems of social interaction that are increasingly recognized to meet the criteria of autistic spectrum disorder (1, 2), a neurodevelopmental disorder. In adults, high rates of psychotic disorders, especially schizophrenia, have been reported (2-5).It is likely that the pathophysiological basis of many psychiatric disorders is heterogeneous involving multiple genes and environmental factors. Therefore, when they occur frequently in association with a defined genetic defect, as in the case of 22q11DS (3, 4, 6, 7), it offers a unique opportunity to identify causative or contributing genes, especially if a good animal model is available. We developed a mouse model of 22q11DS (8), the Df1͞ϩ mouse, which carries a heterozygous deletion encompassing 22 genes. Df1͞ϩ mice recapitulate many of the cardiovascular defects associated with 22q11DS (8), and they also display abnormal behavior, including impaired sensorimotor gating, as measured by prepulse inhibition (PPI) o...

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

Cited by 69 publications

References 38 publications

Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation

UV-mediated Regulation of the Anti-senescence Factor Tbx2

Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome

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