Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression
Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression
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DOI：
10.1038/mp.2008.21
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发表时间：
2009-07-01
影响因子：
11
通讯作者：
Persico, A. M.
中科院分区：
文献类型：
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作者：
Lintas, C.;Sacco, R.;Persico, A. M.
蛋白激酶C酶在信号转导、基因表达调控、细胞分裂分化调控等方面发挥着重要作用。FSI和βII同工酶是PKCβ基因(PRKCB1)选择性剪接的结果，此前发现该基因与自闭症有关。我们在229个单纯性和5个复合性家系中进行了基于家族的关联研究，并对11例自闭症患者和对照组的颞叶皮质灰质中PRKCB1基因的表达进行了尸检研究(BA41/42)。PRKCB1基因单倍型与自闭症显著相关(P<；0.05)，并具有增强型少肽尿症的自闭症内表型(P<；0.05)。根据qPCR，PRKCB1-1和PRKCB1-2亚型的临时皮质PRKCB1基因表达平均降低了35%和31%(P<；0.01和P<；0.05)。PKCβII亚型的蛋白质含量也同样减少了35%(P=0.05)。携带“正常”PRKCB1等位基因的患者具有基因表达降低的特征，而携带自闭症相关等位基因纯合的患者显示出与对照组相当的mRNA水平。全基因组表达分析揭示了PKCβ驱动的基因协调表达的部分中断，包括几种细胞因子。这些结果证实了自闭症与PRKCB1基因变异之间的联系，指出PKCβ在上皮通透性改变中的作用，表明自闭症患者大脑PRKCB1基因表达显著下调，并表明这可能是一种旨在限制正在进行的异常反应免疫过程的代偿性调整。总之，这些数据强调了PKCβ在自闭症发病机制中的潜在作用，并激发了人们对导致自闭症易感性的PRKCB1基因变体的识别和功能特征的兴趣。《分子精神病学》(2009年)14705-718；DOI：10.1038/mp.2008.21；3月4日在线发表
Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and beta II isoenzymes result from the alternative splicing of the PKC beta gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P < 0.05) and have the autistic endophenotype of enhanced oligopeptiduria (P < 0.05). Temporocortical PRKCB1 gene expression was reduced on average by 35 and 31% for the PRKCB1-1 and PRKCB1-2 isoforms (P < 0.01 and < 0.05, respectively) according to qPCR. Protein amounts measured for the PKC beta II isoform were similarly decreased by 35% (P = 0.05). Decreased gene expression characterized patients carrying the 'normal' PRKCB1 alleles, whereas patients homozygous for the autism-associated alleles displayed mRNA levels comparable to those of controls. Whole genome expression analysis unveiled a partial disruption in the coordinated expression of PKC beta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKC beta roles in altered epithelial permeability, demonstrate a significant downregulation of brain PRKCB1 gene expression in autism and suggest that it could represent a compensatory adjustment aimed at limiting an ongoing dysreactive immune process. Altogether, these data underscore potential PKC beta roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability. Molecular Psychiatry (2009) 14, 705-718; doi:10.1038/mp.2008.21; published online 4 March 2008