Caubit Xavier, Gubellini Paolo, Andrieux Joris, Roubertoux Pierre L, Metwaly Mehdi, Jacq Bernard, Fatmi Ahmed, Had-Aissouni Laurence, Kwan Kenneth Y, Salin Pascal, Carlier Michèle, Liedén Agne, Rudd Eva, Shinawi Marwan, Vincent-Delorme Catherine, Cuisset Jean-Marie, Lemaitre Marie-Pierre, Abderrehamane Fatimetou, Duban Bénédicte, Lemaitre Jean-François, Woolf Adrian S, Bockenhauer Detlef, Severac Dany, Dubois Emeric, Zhu Ying, Sestan Nenad, Garratt Alistair N, Lydia Kerkerian-Le Goff, Fasano Laurent
Aix Marseille Univ, CNRS, IBDM, Marseille, France.
Institut de génétique médicale, Hôpital Jeanne de Flandre, CHRU Lille, France.
Nat Genet. 2016 Nov;48(11):1359-1369. doi: 10.1038/ng.3681. Epub 2016 Sep 26.
TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.
TSHZ3编码一种锌指转录因子，最近被定位为在发育中的人类新皮层中表达最高的一组基因模块中的枢纽基因，但其功能仍不清楚。在这里，我们确定TSHZ3是与19q12 - q13.11杂合缺失相关综合征的关键区域，该综合征包括自闭症谱系障碍（ASD）。在Tshz3基因敲除小鼠中，差异表达基因包括大脑皮质投射神经元（CPN）的层特异性标记物，这些基因的人类同源物与ASD密切相关。此外，Tshz3杂合子小鼠在CPN建立的突触处表现出功能变化，并表现出核心的ASD样行为异常。这些发现突出了Tshz3在CPN发育和功能中的重要作用，其改变可解释新定义的TSHZ3缺失综合征中的ASD。
