Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans:: Implications for 22q11 deletion syndrome
Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans:: Implications for 22q11 deletion syndrome
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DOI：
10.1073/pnas.0600206103
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发表时间：
2006-05-16
影响因子：
11.1
通讯作者：
Lindsay, Elizabeth
中科院分区：
文献类型：
--
作者：
Paylor, Richard;Glaser, Beate;Lindsay, Elizabeth
大约35%的22 q11缺失综合征（22 q11 DS）患者，包括DiGeorge和腭心面综合征，发展为精神障碍，主要是精神分裂症和双相情感障碍。我们以前报道，小鼠携带多基因缺失（Df 1）模型22 q11 DS减少前脉冲抑制（PPI），行为异常和精神分裂症内表型。PPI受损与几种精神疾病相关，包括发生在22 q11 DS中的精神疾病，最近，22 q11 DS儿童中报告了PPI降低。在这里，我们已经映射PPI赤字在一个小组的小鼠突变体进行删除，部分重叠DO和定义了PPI的关键区域，包括四个基因。然后，我们使用单基因突变体来识别致病基因。我们发现，PIPI缺陷Df 1/+小鼠是由两个基因，Tbx 1和Gnb 1 l的单倍不足。任何一个基因突变都足以导致PPI降低。Tbx 1是一种转录因子，其突变足以引起22 q11 DS的大部分物理特征，但该基因先前未与行为/精神表型相关。TBX 1单倍不足在精神疾病中的可能作用进一步表明，在一个家庭中，22 q11 DS的表型特征，包括精神疾病，与TBX 1的失活突变分离的鉴定。一个家庭成员患有普格综合征，这是一种与PPI降低有关的自闭症谱系障碍。因此，Tbx 1和Gnb 1 I是22 q11 DS患者中精神疾病的强有力候选者，也是更广泛人群中精神疾病的候选易感基因。
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.