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)
Type
Research Project (R01)
Project #
5R01HD062553-05
Application #
8681206
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Parisi, Melissa
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Samaco, Rodney C; McGraw, Christopher M; Ward, Christopher S et al. (2013) Female Mecp2(+/-) mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum Mol Genet 22:96-109
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
Pitcher, Meagan R; Ward, Christopher S; Arvide, E Melissa et al. (2013) Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function. Hum Mol Genet 22:2626-33
Ward, Christopher S; Arvide, E Melissa; Huang, Teng-Wei et al. (2011) MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J Neurosci 31:10359-70
Samaco, Rodney C; Neul, Jeffrey L (2011) Complexities of Rett syndrome and MeCP2. J Neurosci 31:7951-9
McCauley, Mark D; Wang, Tiannan; Mike, Elise et al. (2011) Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: implication for therapy in Rett syndrome. Sci Transl Med 3:113ra125