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.

Public Health Relevance

The goal of this project is to understand how abnormal function of the brain affects the activity of the autonomic nervous system and how it leads to premature death in Rett syndrome and other disorders of childhood. This understanding will help us better understand problems which affect the ability of the nervous system to automatically control breathing, heart rate, and other functions of this special part of the nervous system. Knowledge gained from this will assist in the development of treatments not only for Rett syndrome and related disorders, but also for other diseases that affect autonomic functioning and which are significant public health problems such as sudden infant death syndrome, familial dysautonomia, multiple system atrophy (a type of parkinsonism), and congenital central hypoventilation syndrome among others.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD062553-04
Application #
8462480
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2010-07-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$343,754
Indirect Cost
$120,479
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Herrera, José A; Ward, Christopher S; Wehrens, Xander H T et al. (2016) Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis. Hum Mol Genet :
Huang, Teng-Wei; Kochukov, Mikhail Y; Ward, Christopher S et al. (2016) Progressive Changes in a Distributed Neural Circuit Underlie Breathing Abnormalities in Mice Lacking MeCP2. J Neurosci 36:5572-86
Ward, Christopher S; Huang, Teng-Wei; Herrera, José A et al. (2016) Loss of MeCP2 Causes Urological Dysfunction and Contributes to Death by Kidney Failure in Mouse Models of Rett Syndrome. PLoS One 11:e0165550
Veeraragavan, Surabi; Wan, Ying-Wooi; Connolly, Daniel R et al. (2016) Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome. Hum Mol Genet 25:3284-3302
Herrera, José A; Ward, Christopher S; Pitcher, Meagan R et al. (2015) Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs. Dis Model Mech 8:363-71
Pitcher, Meagan R; Herrera, José A; Buffington, Shelly A et al. (2015) Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. Hum Mol Genet 24:2662-72
Wang, Jieqi; Wegener, Jan Eike; Huang, Teng-Wei et al. (2015) Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521:E1-4
Yuengert, Rachel; Hori, Kei; Kibodeaux, Erin E et al. (2015) Origin of a Non-Clarke's Column Division of the Dorsal Spinocerebellar Tract and the Role of Caudal Proprioceptive Neurons in Motor Function. Cell Rep 13:1258-71
Glasgow, Stacey M; Zhu, Wenyi; Stolt, C Claus et al. (2014) Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat Neurosci 17:1322-9
Ramirez, Jan-Marino; Ward, Christopher Scott; Neul, Jeffrey Lorenz (2013) Breathing challenges in Rett syndrome: lessons learned from humans and animal models. Respir Physiol Neurobiol 189:280-7

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