Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all live born children and epilepsy in about 0.5%, placing them among the most common known childhood disorders. Despite this high frequency, the molecular and cellular basis for only a very few disorders has been recently elucidated, while the basis of many more remains unknown. Mutations in the transcription factor ARX have been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. As predicted in our first application, mutations of this gene prove to be a relatively common cause of mental retardation and infantile epilepsy based on the wide spectrum of severity already apparent in this group of children and a recurrent mechanism for mutation in at least two of the four polyalanine tracts found in the gene. The developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on data generated from this grant in humans and mice, the following hypotheses have been generated: (1) the type of ARX mutation predicts the phenotype in both hemizygous males and heterozygous females;(2) the phenotype in affected female humans and mice correlates with X-inactivation;and (3) Arx with an expanded poly-A tract results in defects in transcriptional repression, ultimate resulting in mice with seizures and mental retardation. To test these hypotheses, a series of experiments are proposed that will discover the mutation types in a large series of male and female patients with candidate phenotypes and determine X-inactivation status. In this application we will focus on elucidating the mechanism of a poly-A tract mutation in causing the neurologic phenotype, and in further understanding the downstream targets of Arx and their role in normal and abnormal brain development and function. The phenotypes in humans and mutant mice with different ARX/Arx mutations will be analyzed and compared to each other and to overlapping phenotypes caused by mutations of related genes. These studies are expected to provide a greater understanding of how Arx functions in normal and abnormal development, and will contribute to our understanding of the pathogenesis of such common disorders in children as mental retardation, epilepsy, and structural anomalies of the brain.

Public Health Relevance

Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application seeks to understand how one gene, ARX, commonly causes childhood epilepsy and mental retardation. Ultimately we expect these studies will lead to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Riddle, Robert D
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Children's Hospital of Philadelphia
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Sunnen, C Nicole; Simonet, Jacqueline C; Marsh, Eric D et al. (2014) Arx is required for specification of the zona incerta and reticular nucleus of the thalamus. J Neuropathol Exp Neurol 73:253-61
Mirzaa, Ghayda M; Millen, Kathleen J; Barkovich, A James et al. (2014) The Developmental Brain Disorders Database (DBDB): a curated neurogenetics knowledge base with clinical and research applications. Am J Med Genet A 164A:1503-11
Cho, Ginam; Lim, Youngshin; Cho, Il-Taeg et al. (2014) Arx together with FoxA2, regulates Shh floor plate expression. Dev Biol 393:137-48
Bourgeois, Elliot B; Johnson, Brian N; McCoy, Almedia J et al. (2014) A toolbox for spatiotemporal analysis of voltage-sensitive dye imaging data in brain slices. PLoS One 9:e108686
Tully, Hannah M; Dobyns, William B (2014) Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet 57:359-68
Nasrallah, MacLean Pancoast; Cho, Ginam; Simonet, Jacqueline C et al. (2012) Differential effects of a polyalanine tract expansion in Arx on neural development and gene expression. Hum Mol Genet 21:1090-8
Cho, Ginam; Nasrallah, MacLean P; Lim, Youngshin et al. (2012) Distinct DNA binding and transcriptional repression characteristics related to different ARX mutations. Neurogenetics 13:23-9
Paciorkowski, Alex R; Thio, Liu Lin; Rosenfeld, Jill A et al. (2011) Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function. Eur J Hum Genet 19:1238-45
Mastracci, Teresa L; Wilcox, Crystal L; Arnes, Luis et al. (2011) Nkx2.2 and Arx genetically interact to regulate pancreatic endocrine cell development and endocrine hormone expression. Dev Biol 359:1-11
Lysko, Daniel E; Putt, Mary; Golden, Jeffrey A (2011) SDF1 regulates leading process branching and speed of migrating interneurons. J Neurosci 31:1739-45

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