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

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 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...

Realistic expectations of prepulse inhibition in translational models for schizophrenia research

“…The specificity of the linkage of the model with schizophrenia, and hence with PPI deficits in schizophrenia, must come from the construct. For example, the finding of PPI deficits in a murine model of 22q11 deletion syndrome (22q11DS) links this model to PPI deficits in schizophrenia (Paylor et al 2006;Sobin et al 2005a, b), on the basis of the clinical relationship between 22q11DS and schizophrenia. Without this clinical relationship, this would just be a mouse with low PPI, and the model would most likely be a "false positive" for the schizophrenia phenotype.…”

Advances in endophenotyping schizophrenia

“…Normal inhibition in these measures is regulated by specific forebrain circuits, and these circuits in turn are controlled by a large number of genes. For example, PPI deficits are detected in Huntington's disease (43), 22q11 deletion syndrome (44) and fragile-X syndrome (45), and in animal models of each of these disorders (45)(46)(47).…”

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome

“…TBX1 has been shown to play an important role in congenital heart defects and other anomalies related to pharyngeal apparatus development in 22q11DS (Lindsay 2001). Interestingly, a recent study suggests TBX1 may play a role in behaviour as well (Paylor et al 2006). …”