KCNJ11 Diabetes: Exploring the Role of KATP Channels in the Brain

描述(由申请人提供)：单基因糖尿病是一组疾病，由胰腺中产生胰岛素的β细胞的适当功能所必需的若干基因中的任何一种突变引起。一些患者在编码蛋白质的基因上发生了突变，这些蛋白质也在胰腺外组织中表达，因此除了糖尿病之外，还有其他特征，如智力障碍。据估计，单基因形式的糖尿病可能占所有糖尿病病例的2%。在一岁前被诊断为糖尿病的情况很少见，但这类患者尤其可能有潜在的单基因原因。芝加哥大学新生儿糖尿病注册中心现在收录了300多名一岁前确诊的糖尿病患者的临床和遗传信息。这些病例中最大的一组在新生儿糖尿病最常见的遗传原因中存在突变：编码三磷酸腺苷敏感钾(KATP)通道Kir6.2亚单位的KCNJ11基因的激活突变，KATP通道在胰岛素分泌中起关键作用。以前接受过胰岛素治疗的KCNJ11相关新生儿糖尿病患者在使用磺脲类药物(通常是格列本脲)治疗时，表现出良好的血糖控制和最小的低血糖，这些药物可以促进过度激活的突变通道的关闭。由于突变的KATP通道在大脑中的表达，这些患者还表现出一系列神经发育障碍。激活KCNJ11突变的受试者表现出各种神经缺陷，从那些有轻度问题(如多动)的人，到中度言语和运动延迟并随后出现中度认知障碍和视觉运动失调的病例，以及罕见的突变，导致严重的全球发育障碍，进展为智力低下和癫痫。事实上，KATP通道在大脑中广泛表达，这表明它们可能在几种不同的功能中发挥作用；然而，这些通道的神经功能仍然知之甚少。重要的是，我们小组和其他人进行的有限研究表明，尽管磺脲类药物治疗改善了这些患者的神经功能，但他们仍然受到损害。患有KCNJ11相关糖尿病的受试者提供了一个无与伦比的机会来研究特定干扰KATP通道的人类模型，KATP通道在大脑中广泛表达。因此，在这项应用中，我们提出了以下目标：1)表征KCNJ11糖尿病患者的神经发育和眼球跟踪障碍；2)表征KCNJ11糖尿病患者的神经解剖异常；3)表征KCNJ11糖尿病患者的异常睡眠模式。18岁或18岁以上的受试者将接受详细的脑成像、多导睡眠图、视频眼震图、神经心理学和神经认知评估。建立大脑内功能失调的KATP通道的临床、神经发育和解剖学后遗症可能为我们提供对人类生理学和病理学的独特见解。此外，我们的研究对患有KCNJ11突变的儿童有明显的影响。通过更详细和更全面地了解他们面临的斗争，临床医生将更好地准备提供他们所需的许多支持，包括多专业治疗以及医疗干预。由于使用磺脲类药物的大剂量单一疗法似乎导致有限的神经改善，通过拟议的研究获得的数据将成为未来替代或额外医疗疗法试验的基础，这些疗法可能在纠正大脑内的通道功能方面更有效。拟议的研究不仅将揭示有关经络在大脑中的作用的更多细节，而且还将允许验证几种拟议的措施，这些措施可用于在未来的干预研究中跟踪改善(或缺乏)。这些患者与其他神经发育和行为障碍有许多共同的临床特征，包括运动协调和认知障碍、多动和注意力不集中等。我们预计，这些研究将阐明KATP通道在脑内的作用，并为未来研究KATP通道在许多其他神经发育障碍中的作用奠定基础。

DESCRIPTION (provided by applicant): Monogenic diabetes is a group of disorders caused by mutations in any one of a number of genes essential for the appropriate function of the insulin producing beta-cells in the pancreas. Some patients have mutations in genes that encode proteins that are also expressed in extra-pancreatic tissues and thus have other features in addition to the diabetes, such as intellectual impairment. Estimates suggest that monogenic forms of diabetes could represent as much as 2% of all diabetes cases. Diabetes diagnosed before one year of age is a rare occurrence but such patients are especially likely to have an underlying monogenic cause. The University of Chicago Neonatal Diabetes Registry now includes clinical and genetic information on over 300 subjects with diabetes diagnosed prior to one year of age. The largest subgroup of these cases have mutations in the most common genetic cause of neonatal diabetes: activating mutations in the gene KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, which plays a critical role in insulin secretion. Patients with KCNJ11-related neonatal diabetes who were previously treated with insulin exhibit clinically excellent glucose control with minimal hypoglycemia when treated with sulfonylureas (usually glyburide) that promote closure of overly activated mutant channels. Because of the expression of mutated KATP channels in the brain, these patients also exhibit a spectrum of neurodevelopmental disability. Subjects with activating KCNJ11 mutations display a variety of neurological defects, from those with mild problems such as hyperactivity, to cases with moderate speech and motor delay with subsequent moderate cognitive impairment and visuomotor dis-coordination, as well as rare mutations causing severe global developmental disability progressing to mental retardation and seizures. The fact that KATP channels are found widely expressed throughout the brain suggests that they are likely to have roles in several different capacities; however, the neuronal function of these channels remains poorly understood. Importantly, limited study by our group and others has suggested that although sulfonylurea treatment improves the neurological functioning in these patients, they remain impaired. Subjects with KCNJ11-related diabetes represent an unparalleled opportunity to investigate a human model of specific disruption the KATP channels that are expressed widely within the brain. In this application, we thus propose the following Aims: 1) To characterize the neurodevelopmental and eye tracking impairments in KCNJ11 diabetes; 2) To characterize neuroanatomical abnormalities in KCNJ11 diabetes; 3) To characterize abnormal sleep patterns in KCNJ11 diabetes. Subjects 18 years of age or older will undergo detailed brain imaging, polysomnography, videonystagmography, neuropsychological and neurocognitive assessments. Establishing the clinical, neurodevelopmental and anatomical sequelae of dysfunctional KATP channels within the brain may offer a unique insight into human physiology and pathology. In addition, our studies have clear implications for children with KCNJ11 mutations. By gaining a more detailed and comprehensive understanding of the struggles they face, clinicians will be better equipped to provide the many supports they require, including multi-specialty therapies as well as medical intervention. Since high dose monotherapy with sulfonylureas appears to result in limited neurological improvement, the data gained through the proposed studies will form the basis for future trials of alternative or additional medical treatments that may be more effective in regards to correcting channel functioning within the brain. The proposed studies will not only reveal much detail about the role of the channels in the brain but will also allow for validation o the several proposed measures that could be utilized to track improvement (or lack thereof) in future interventional studies. These patients have many clinical characteristics in common with other neurodevelopmental and behavioral disorders including motor coordination and cognitive deficits, hyperactivity and inattention, among others. We anticipate that these studies will elucidate the role of KATP channels within the brain and will also lay the groundwork for future studies into the role of KATP channels in many other neurodevelopmental disorders.