Characterization of autonomic dysfunction in Rett syndrome & other MECP2 disorder

描述（由申请人提供）：编码MeCP2 （MeCP2）的x连锁基因突变导致女孩Rett综合征（RTT）和男孩严重先天性脑病。尽管认知障碍和神经功能障碍是这些疾病的标志，受影响的个体也有许多自主神经功能的破坏。患有RTT的女孩有高度不规则的呼吸和心律异常，包括校正QT间期延长和搏动变异性降低。RTT中四分之一的死亡是突然和意外的；自主神经异常被认为是导致他们死亡的原因。MECP2基因突变和先天性脑病的男孩有许多自主神经异常，包括心动过缓、呼吸暂停和呼吸停止，导致在生命的前三年死亡。缺乏MeCP2功能（Mecp2null/Y）的雄性小鼠寿命缩短，并重现许多RTT的临床特征，包括自主神经变化，如呼吸异常和较长的QTc。然而，在死亡过程中观察到的生理变化之间的关系仍然未知。我们最近发现，去除不同解剖区域的MeCP2功能可以重现Mecp2null/Y动物的过早死亡。这些发现导致了一种假设，即特定神经元群中MeCP2功能的丧失会导致继发于自主神经功能障碍的过早死亡。这项工作的目的是确定死亡之前和导致死亡的生理变化，并确定MeCP2缺失导致自主神经功能障碍和死亡的关键解剖区域。具体目的是：1)确定Mecp2null/Y动物的生理变化。了解各种生理变化的时间关系将有助于深入了解死亡的主要原因。2)使用条件敲除方法确定正常寿命和生理需要MeCP2功能的关键解剖区域。这将确定自主控制需要MeCP2功能的解剖区域；此外，阐明先于或导致过早死亡的特定生理异常将提示因果关系。3)确定恢复MeCP2功能能够挽救早死和改善生理的解剖区域。从该项目获得的信息将有助于了解MECP2相关疾病患者死亡和自主神经功能障碍的潜在原因。此外，它将进一步理解和定义控制关键自主神经功能的神经元回路。这些知识不仅有助于开发RTT和其他MECP2相关疾病的治疗方法，而且还将提供机制理解，可能有助于深入了解其他具有呼吸、心功能或自主神经控制改变的临床疾病，如婴儿猝死、先天性低通气综合征、家族性自主神经异常和多系统萎缩。

DESCRIPTION (provided by applicant): Mutations in the X-linked gene that encodes MeCP2 (MECP2) cause Rett Syndrome (RTT) in girls and severe congenital encephalopathy in boys. Although cognitive impairment and neurological dysfunction are hallmarks of these disorders, affected individuals also have disruption of many autonomic functions. Girls with RTT have highly irregular breathing and abnormalities in cardiac rhythm including prolonged corrected QT interval and decreased beat-to-beat variability. One quarter of deaths in RTT are sudden and unexpected; autonomic abnormalities are believed to underlie their deaths. Boys with mutations in MECP2 and congenital encephalopathy have a number of autonomic abnormalities including bradycardia, apnea, and respiratory arrest resulting in death in the first three years of life. Male mice lacking MeCP2 function (Mecp2null/Y) have shortened lifespan and reproduce many clinical features of RTT including autonomic changes such as breathing abnormalities and long QTc. However, the relationship between the physiological changes observed during the progression towards death remains unknown. We have recently discovered that removing MeCP2 function from distinct anatomical regions can reproduce the premature death seen in Mecp2null/Y animals. These findings lead to the hypothesis that loss of MeCP2 function within specific neuronal populations leads to premature death secondary to autonomic dysfunction. The goal of this work is to determine the physiological changes that precede and lead to death and to identify key anatomical regions in which loss of MeCP2 leads to autonomic dysfunction and death. The specific aims are: 1) Determine the physiological changes in Mecp2null/Y animals. Understanding the temporal relationship of various physiological changes will provide insight into the primary cause of death. 2) Define critical anatomical regions that require MeCP2 function for normal lifespan and physiology using a conditional knock-out approach. This will determine anatomical regions in which MeCP2 function is required for autonomic control; furthermore, elucidation of specific physiological abnormalities that precede or lead to premature death will suggest causality. 3) Identify anatomical regions in which restoring MeCP2 function is able to rescue premature death and improve physiology. The information obtained from this project will work towards an understanding of the underlying causes of death and autonomic dysfunction in humans with MECP2 related disorders. In addition, it will further the understanding and definition of neuronal circuits that control key autonomic functions. This knowledge will not only be useful in developing therapies for RTT and other MECP2 related disorders but will also provide mechanistic understanding that might give insight into other clinical disorders that have alterations in respiration, cardiac function, or autonomic control, such as sudden infant death, congenital hypoventilation syndrome, familial dysautonomia, and multiple system atrophy.