期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 20, 页码 7729-7734出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0600206103
关键词
mouse model; psychiatric disease; DiGeorge syndrome; sensorimotor gating
资金
- MRC [G9810900, G9309834] Funding Source: UKRI
- Medical Research Council [G9309834, G9810900] Funding Source: researchfish
- Medical Research Council [G9309834, G9810900] Funding Source: Medline
- NIDCD NIH HHS [K08 DC006671] Funding Source: Medline
- Telethon [TCP04006] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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.
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