原发性夜间遗尿症患儿多巴胺受体D4启动子区基因多态性与睡眠异常的多模态磁共振成像研究

Primary nocturnal enuresis (PNE) is a kind of disease with complex genetic effects. The exploration of pathogenesis and effective treatment method of PNE is important to improve mental health of children and their parients. Our preliminary studies have found that there are significant differences in the frequency of -616 C/G allele in dopamine receptor D4 (DRD4) between children suffering primary nocturnal enuresis (PNE) and normal control group, which will influence the structure, γ-aminobutyric acid (GABA) concentration and functional connectivities of thalamus in PNE children. In addition, the cerebral oxygen consumption was higher in PNE children than in controls. We hypothesize that the DRD4-616C/G polymorphism in the promoter region not only elevate the GABA concentration of thalamus, weakens thalamic cortical functional connectivity in sleeping PNE children, but also affects axon development in PNE children and elevate cerebral oxygen consumption, which leads to relative hypoxia in PNE children during sleep. The abnormal thalamic GAGA levels, thalamic cortical functional disconnectivity and hypoxia lead to nocturnal enuresis. To verify this hypothesis, we will sequence the DRD4 promoter region to identify gene polymorphisms in PNE children and controls, along with MEGA-PRESS MRS scaning, magnetic resonance neurite direction dispersion and densityimaging (NODDI), the T2 relaxation of spin labeled (TRUST) and sleep state EEG-fMRI synchronous scanning to clarify the mechanism of the effects of DRD4 polymorphism on GABA concentration, cerebral micro structure, oxygen metabolism and sleep state thalamocortical functional connectivity of PNE children. This study will reveal the genetic and neural mechanism of PNE pathogenesis, with a focus on DRD4. The study findings will provide new ideas for the prevention and treatment of PNE.

原发性夜间遗尿症（PNE）遗传效应显著，探索PNE遗传机制对PNE的治疗有重要意义。我们前期研究发现PNE患儿睡眠期间脑氧耗量偏高，且多巴胺受体D4（DRD4）基因启动子区-616位点SNP影响PNE患儿脑微结构、丘脑GABA浓度及静息态功能连接。由此我们提出工作假说：DRD4启动子区基因多态性使PNE患儿丘脑GABA浓度升高、并影响PNE患儿神经突发育，导致其睡眠期间脑氧耗量偏高及丘脑-皮层连接减弱，致使夜间遗尿发生。为验证该假说，我们计划检测PNE患儿及正常对照儿童DRD4启动子区基因多态性，结合MEGA-PRESS、NODDI、睡眠态TRUST及EEG-fMRI磁共振扫描，明确DRD4启动子区基因多态性对PNE患儿脑神经递质、微结构、睡眠态氧代谢及丘脑动态功能连接的影响。本研究将从DRD4启动子区基因多态性这个新视点揭示PNE发病的遗传和神经机制，为PNE精准治疗提供新思路、新靶点。

我们的NODDI研究发现，PNE患儿上纵束ODI值偏低，内囊和丘脑前辐射ODI偏高；内囊及胼胝体NDI值偏低，上纵束NDI值偏高；我们的睡眠态EEG-fMRI研究也表明：PNE患儿NREM睡眠期间丘脑-额叶功能连接异常及丘脑内部的功能连接异常与他们的睡眠结构异常及脑电觉醒指数异常显著相关；我们的MRS研究表明：DRD4基因-616位点携带C等位基因的PNE患儿丘脑GABA水平显著高于非携带者，而且携带C等位基因的PNE患儿，丘脑GABA水平与唤醒难度相关。上述研究结果初步揭示了DRD4启动子区基因多态性对PNE患儿神经递质浓度、神经突密度和神经突方向及睡眠态丘脑-皮层动态功能连接的影响，及其与PNE患儿夜间遗尿症状和睡眠监测结果的相关性。我们的研究从DRD4这个新视点揭示了PNE发病的神经及遗传机制，从遗传、分子、功能和代谢的层面深入阐述PNE发生、发展的机理，进而可能筛选并确定用于高危个体或人群检测的易感基因和遗传标记，为PNE的个体化精准治疗提供新的思路，具有重要的理论意义和实用价值。

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