Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome, Proc Natl Acad Sci USA 103, 7729-7734

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2006; 103(20):7729-34. DOI: 10.1073/pnas.0600206103
Source: PubMed

ABSTRACT 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 Df1/+ 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 behavioral/psychiatric 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.

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Available from: Annalisa Mupo, Sep 28, 2015
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    • "TBX1 haploinsufficiency has long been known to be crucial in the aetiology of 22q11DS. Mutation analysis has revealed frameshift and missense mutations of TBX1 in patients with the 22q11DS-phenotype, but no detectable deletion [4,24,25]. Animal model experimental evidence suggests that Tbx1 is required for normal heart development [26,27]; however, no unequivocal mutation of TBX1 has been discovered in isolated CTDs patients. Tbx1 is expressed in the secondary heart field (SHF) and positively regulates SHF cell proliferation and contribution to the muscle layer of outflow tract (OFT), of which the myocardium derives from the SHF [28-30]. "
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    ABSTRACT: Background TBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of TBX1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of TBX1 and CRKL in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations. Methods We enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by in vitro transfection and luciferase experiments and computer modelling. Results Screening of the TBX1 coding sequence identified a de novo missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1E129K variant almost lost transactivation activity. The TBX1G310S variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX1-DNA interaction. No mutation of CRKL gene was found. Conclusions These observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.
    BMC Medical Genetics 07/2014; 15(1):78. DOI:10.1186/1471-2350-15-78 · 2.08 Impact Factor
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    • "Data show that TBX1 haploinsufficiency is responsible for cardiovascular, craniofacial, thymic, and parathyroid defects in mouse models of 22q11.2 microdeletion.94 "
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    ABSTRACT: The 22q11.2 deletion syndrome (22q11DS) is caused by an autosomal dominant microdeletion of chromosome 22 at the long arm (q) 11.2 band. The 22q11DS is among the most clinically variable syndromes, with more than 180 features related with the deletion, and is associated with an increased risk of psychiatric disorders, accounting for up to 1%-2% of schizophrenia cases. In recent years, several genes located on chromosome 22q11 have been linked to schizophrenia, including those encoding catechol-O-methyltransferase and proline dehydrogenase, and the interaction between these and other candidate genes in the deleted region is an important area of research. It has been suggested that haploinsufficiency of some genes within the 22q11.2 region may contribute to the characteristic psychiatric phenotype and cognitive functioning of schizophrenia. Moreover, an extensive literature on neuroimaging shows reductions of the volumes of both gray and white matter, and these findings suggest that this reduction may be predictive of increased risk of prodromal psychotic symptoms in 22q11DS patients. Experimental and standardized cognitive assessments alongside neuroimaging may be important to identify one or more endophenotypes of schizophrenia, as well as a predictive prodrome that can be preventively treated during childhood and adolescence. In this review, we summarize recent data about the 22q11DS, in particular those addressing the neuropsychiatric and cognitive phenotypes associated with the deletion, underlining the recent advances in the studies about the genetic architecture of the syndrome.
    Neuropsychiatric Disease and Treatment 12/2013; 9:1873-1884. DOI:10.2147/NDT.S52188 · 1.74 Impact Factor
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    • "However, under some circumstances, mice with partial hearing loss can show reduced startle thresholds and elevated startle amplitudes in acoustic startle testing [29], perhaps because central auditory adaptation to the reduction in peripheral input leads to hyperacusis for loud sounds. Better evidence for normal hearing in Df1/+ mice was provided in [24] based on frequency-specific distortion-product otoacoustic emission (DPOAE) testing, which is generally an excellent means of detecting peripheral auditory abnormalities including middle ear problems. However, the DPOAE testing in that study was performed on only 6 Df1/+ mice, and apparently only on one ear in each animal. "
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    ABSTRACT: 22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM.
    PLoS ONE 11/2013; 8(11):e80104. DOI:10.1371/journal.pone.0080104 · 3.23 Impact Factor
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