Lintas C, Sacco R, Garbett K, Mirnics K, Militerni R, Bravaccio C, Curatolo P, Manzi B, Schneider C, Melmed R, Elia M, Pascucci T, Puglisi-Allegra S, Reichelt K-L, Persico A M
Laboratory of Molecular Psychiatry and Neurogenetics, University Campus Bio-Medico, Rome, Italy.
Mol Psychiatry. 2009 Jul;14(7):705-18. doi: 10.1038/mp.2008.21. Epub 2008 Mar 4.
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 betaII isoenzymes result from the alternative splicing of the PKCbeta 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 PKCbetaII 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 PKCbeta-driven genes, including several cytokines. These results confirm the association between autism and PRKCB1 gene variants, point toward PKCbeta 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 PKCbeta roles in autism pathogenesis and spur interest in the identification and functional characterization of PRKCB1 gene variants conferring autism vulnerability.
蛋白激酶C酶在信号转导、基因表达调控以及细胞分裂与分化控制中发挥着重要作用。fsI和βII同工酶是PKCβ基因（PRKCB1）可变剪接的产物，此前发现该基因与自闭症有关。我们在229个单病例家庭和5个多病例家庭中进行了基于家系的关联研究，并对11名自闭症患者和对照者颞叶皮质灰质（BA41/42）中的PRKCB1基因表达进行了尸检研究。PRKCB1基因单倍型与自闭症显著相关（P<0.05），并具有寡肽尿增强的自闭症内表型（P<0.05）。根据定量聚合酶链反应（qPCR），PRKCB1-1和PRKCB1-2同工型的颞叶皮质PRKCB1基因表达平均分别降低了35%和31%（分别为P<0.01和<0.05）。PKCβII同工型的蛋白质含量同样降低了35%（P=0.05）。基因表达降低是携带“正常”PRKCB1等位基因患者的特征，而自闭症相关等位基因纯合的患者显示出与对照者相当的mRNA水平。全基因组表达分析揭示了PKCβ驱动基因（包括几种细胞因子）的协调表达存在部分破坏。这些结果证实了自闭症与PRKCB1基因变异之间的关联，指出了PKCβ在上皮通透性改变中的作用，证明了自闭症患者大脑PRKCB1基因表达显著下调，并表明这可能代表一种旨在限制正在进行的反应性免疫过程的代偿性调节。总之，这些数据强调了PKCβ在自闭症发病机制中的潜在作用，并激发了对赋予自闭症易感性的PRKCB1基因变异进行鉴定和功能表征的兴趣。
