Rett syndrome (RTT), a leading cause of mental retardation in females, causes cognitive, motor, and social regression after an initial period of normal development. Movement disorders and stereotypical hand behavior are distinctive features in these patients. RTT is caused by loss of function mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor that binds to methylated CpG dinucleotides. Abnormalities of the basal ganglia and dopaminergic transmission have been described in RTT, but the molecular events leading from mutation of MeCP2 to the neurologic deficits of this disorder are unknown. I am interested in the role of the basal ganglia in RTT and the function of MeCP2 and DNA methylation in these sub cortical structures. I hypothesize that specific neuronal abnormalities of gene expression in the basal ganglia are at the root of the movement disorders of RTT. I propose to use Mecp2 mutant mice generated in Dr. Zoghbi 'S lab to identify genes that are misregulated in the basal ganglia. To pursue this study, I will (1) analyze motor and stereotypical behavior in mutant mice; (2) compare gene expression in the striatum and brainstem of wild-type and mutant mice using a candidate gene approach and cDNA micro array experiments; (3) study the effects of methyl-donors known to increase DNA-methylation on the mutant mouse phenotype. These studies will begin to shed light on the pathogenesis of RTT, and lend insight into the biology of mental retardations, movement disorders, and the role of DNA methylation in brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS043969-01
Application #
6486508
Study Section
Special Emphasis Panel (ZRG1-F01 (20))
Program Officer
Finkelstein, Robert
Project Start
2002-05-01
Project End
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$54,352
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Moretti, Paolo; Levenson, Jonathan M; Battaglia, Fortunato et al. (2006) Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci 26:319-27
Moretti, P; Sahoo, T; Hyland, K et al. (2005) Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 64:1088-90
Moretti, Paolo; Hedera, Peter; Wald, John et al. (2005) Autosomal recessive primary generalized dystonia in two siblings from a consanguineous family. Mov Disord 20:245-7
Moretti, Paolo; Bouwknecht, J Adriaan; Teague, Ryan et al. (2005) Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 14:205-20
Moretti, P; Lieberman, A P; Wilde, E A et al. (2004) Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology 62:1865-8
Moretti, Paolo; Blazo, Maria; Garcia, Leonardo et al. (2004) Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy. Am J Med Genet A 124A:392-6