Paylor, R and Glaser, B and Mupo, A and Ataliotis, P and Spencer, C and Sobotka, A and Sparks, C and Choi, CH and Oghalai, J and Curran, S and Murphy, KC and Monks, S and Williams, N and O'Donovan, MC and Owen, MJ and Scambler, PJ and Lindsay, E (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome. P NATL ACAD SCI USA , 103 (20) 7729 - 7734. 10.1073/pnas.0600206103.
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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 DO and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PIPI 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 Gnb1I are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.
|Title:||Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome|
|Keywords:||mouse model, psychiatric disease, DiGeorge syndrome, sensorimotor gating, DIGEORGE-SYNDROME REGION, CARDIO-FACIAL/DIGEORGE-SYNDROME, HIGH-FUNCTIONING AUTISM, CARDIOVASCULAR DEFECTS, PREPULSE INHIBITION, CHROMOSOMAL DELETIONS, SYNDROME PHENOTYPE, ASPERGER-SYNDROME, FACIAL SYNDROME, SCHIZOPHRENIA|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Genes, Development and Disease > ICH - Molecular Medicine Unit|
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