Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all liveborn children and epilepsy in about 0.5%, placing them among the most common childhood disorders known. Despite the high frequency, the molecular and cellular basis for some of the underlying disorders has been elucidated only recently, while the basis of many more remains unknown. Mutations in the transcription factor ARX have recently been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. We anticipate that mutations of this gene will 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 developmental problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on preliminary data from 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) Arx is necessary for normal radial cell migration of projection neurons from the neocortical ventricular zone, and for nonradial migration of inhibitory interneurons and development of the basal ganglia from the ganglionic eminence; and (3) 5' polyalanine expansions of Arx seen in some patients with infantile seizures and mental retardation cause Arx aggregation in the nucleus, which results in loss of Arx function or renders the protein toxic to vulnerable neurons. 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. In addition, a mouse will be generated with LoxP sites surrounding exon 2, allowing for the specific deletion of Arx in either the neocortex or the ganglionic eminence. Finally, mice with an expansion of a polyalanine track, mimicking a common human mutation of ARX will be constructed. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046616-03
Application #
7194354
Study Section
Special Emphasis Panel (ZRG1-BDCN-F (02))
Program Officer
Riddle, Robert D
Project Start
2005-02-15
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$447,910
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Simonet, Jacqueline C; Sunnen, C Nicole; Wu, Jue et al. (2015) Conditional Loss of Arx From the Developing Dorsal Telencephalon Results in Behavioral Phenotypes Resembling Mild Human ARX Mutations. Cereb Cortex 25:2939-50
Lim, Youngshin; Cho, Il-Taeg; Schoel, Leah J et al. (2015) Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts. Ann Neurol 78:679-96
Colasante, Gaia; Simonet, Jacqueline C; Calogero, Raffaele et al. (2015) ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c. Cereb Cortex 25:322-35
Hansen, Jeanne; Snow, Chelsi; Tuttle, Emily et al. (2015) De novo mutations in SIK1 cause a spectrum of developmental epilepsies. Am J Hum Genet 96:682-90
Paciorkowski, Alex R; McDaniel, Sharon S; Jansen, Laura A et al. (2015) Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly. Epilepsia 56:422-30
Tully, Hannah M; Dobyns, William B (2014) Infantile hydrocephalus: a review of epidemiology, classification and causes. Eur J Med Genet 57:359-68
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
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

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