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

描述（由申请人提供）：单基因糖尿病是由胰腺中产生胰岛素的β细胞的适当功能所必需的许多基因中的任何一个突变引起的一组疾病。一些患者的基因突变编码蛋白质，这些蛋白质也在胰腺外组织中表达，因此除了糖尿病之外，还具有其他特征，例如智力障碍。据估计，单基因型糖尿病可能占所有糖尿病病例的2%。一岁前诊断出糖尿病是罕见的，但这类患者特别可能有潜在的单基因原因。芝加哥大学新生儿糖尿病登记处现在包括300多名一岁前被诊断为糖尿病的患者的临床和遗传信息。这些病例中最大的亚群在新生儿糖尿病最常见的遗传原因中发生突变：KCNJ11基因的激活突变，该基因编码atp敏感钾（KATP）通道的Kir6.2亚基，在胰岛素分泌中起关键作用。先前接受胰岛素治疗的kcnj11相关新生儿糖尿病患者，在接受磺脲类药物（通常是格列本脲）治疗后，表现出临床优异的血糖控制，低血糖最低。磺脲类药物可促进过度激活的突变通道的关闭。由于大脑中突变的KATP通道的表达，这些患者也表现出神经发育障碍的频谱。激活KCNJ11突变的受试者表现出各种各样的神经缺陷，从轻度问题如多动，到中度言语和运动迟缓，随后出现中度认知障碍和视觉运动不协调，以及罕见的突变，导致严重的整体发育障碍进展为智力迟钝和癫痫发作。事实上，发现KATP通道在整个大脑中广泛表达，这表明它们可能在几种不同的能力中发挥作用；然而，这些通道的神经元功能仍然知之甚少。重要的是，我们小组和其他人的有限研究表明，尽管磺脲类药物治疗改善了这些患者的神经功能，但它们仍然受损。kcnj11相关糖尿病患者为研究大脑内广泛表达的KATP通道特异性破坏的人类模型提供了无与伦比的机会。因此，我们提出以下目的：1)表征KCNJ11糖尿病患者的神经发育和眼动追踪障碍；2)探讨KCNJ11型糖尿病的神经解剖学异常；3)了解KCNJ11糖尿病患者睡眠模式异常的特征。18岁或以上的受试者将接受详细的脑成像、多导睡眠图、视频眼球震颤图、神经心理学和神经认知评估。建立脑内功能失调的KATP通道的临床，神经发育和解剖学后遗症可能为人类生理学和病理学提供独特的见解。此外，我们的研究对KCNJ11突变的儿童有明确的启示。通过更详细和全面地了解他们所面临的困难，临床医生将更好地为他们提供所需的许多支持，包括多专业治疗和医疗干预。由于使用磺脲类药物进行大剂量单药治疗似乎对神经系统的改善有限，因此，通过拟议的研究获得的数据将构成未来替代或额外药物治疗试验的基础，这些药物治疗可能在纠正脑内通道功能方面更有效。拟议的研究不仅将揭示大脑中通道作用的许多细节，而且还将允许验证几个拟议的措施，这些措施可以用于跟踪未来介入研究中的改善（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缺陷、多动和注意力不集中等。我们预计这些研究将阐明KATP通道在大脑中的作用，也将为未来研究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.