Ning Zhenfei, Williams John M, Kumari Romika, Baranov Pavel V, Moore Tom
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
Front Psychiatry. 2019 Jun 18;10:416. doi: 10.3389/fpsyt.2019.00416. eCollection 2019.
Autism is a genetically complex neurobehavioral disorder with a population prevalence of more than 1%. Cerebellar abnormalities, including Purkinje cell deficits in the vermis, are consistently reported, and rodent models of cerebellar dysfunction exhibit features analogous to human autism. We previously analyzed the regulation and expression of the pseudoautosomal region 2 gene , which is adjacent to X chromosome-linked , a known autism susceptibility gene. is a regulator of branching morphogenesis and is strongly expressed in Purkinje cells. We previously showed that mouse is not expressed in cerebellar vermis lobules VI-VII and X, regions which exhibit significant Purkinje cell loss or abnormalities in autism. However, these lobules have relatively high expression of , which encodes a neurotrophin receptor implicated in autism. We propose a mechanism whereby inappropriate expression in these lobules could interact with TrkB and p75NTR signaling pathways resulting in Purkinje cell pathology. We report preliminary characterization of X and Y chromosome-linked regulatory sequences upstream of , which are polymorphic in the general population. We suggest that an OREG-annotated region on chromosome Yq12 ∼60 kb from acts as a silencer of Y-linked expression. Deletion of a β-satellite repeat, or alterations in chromatin structure in this region due to -acting factors, could affect the proposed silencing function, leading to reactivation and inappropriate expression of Y-linked . This proposed male-specific mechanism could contribute to the male bias in autism prevalence.
自闭症是一种具有复杂遗传因素的神经行为障碍，在人群中的患病率超过1%。小脑异常，包括蚓部浦肯野细胞缺失，一直被报道，并且小脑功能障碍的啮齿动物模型表现出与人类自闭症相似的特征。我们之前分析了假常染色体区域2基因的调控和表达，该基因与X染色体连锁的一个已知自闭症易感基因相邻。OREG是分支形态发生的调节因子，在浦肯野细胞中强烈表达。我们之前表明，小鼠OREG在小脑蚓部小叶VI-VII和X中不表达，这些区域在自闭症中表现出明显的浦肯野细胞丢失或异常。然而，这些小叶具有相对较高的TrkB表达，TrkB编码一种与自闭症有关的神经营养因子受体。我们提出了一种机制，即这些小叶中不适当的OREG表达可能与TrkB和p75NTR信号通路相互作用，导致浦肯野细胞病变。我们报告了OREG上游X和Y染色体连锁调控序列的初步特征，这些序列在普通人群中具有多态性。我们认为，位于Yq12上距OREG约60 kb的一个OREG注释区域作为Y连锁OREG表达的沉默子。β-卫星重复序列的缺失，或由于顺式作用因子导致该区域染色质结构的改变，可能会影响所提出的沉默功能，导致Y连锁OREG的重新激活和不适当表达。这种提出的男性特异性机制可能导致自闭症患病率的男性偏向。
