This is a revised application for a competitive renewal of a grant to study the molecular mechanisms of imprinting disorders. Prader-Willi syndrome (PWS) is a devastating, complex developmental and neurobehavioral disorder which results from loss of paternal imprinted gene expression at chromosome 15q11-q13. The investigator and others have defined a series of paternally expressed imprinted genes in this chromosome region and the syntenic mouse region in chromosome 7C. The investigator has recently developed a novel mouse model for PWS, and Angelman syndrome (AS), in which a transgene insertion has deleted all the PWS/AS homologous genes. A severe neonatal failure-to-thrive, typical of PWS in humans, occurs on paternal inheritance, but the transgenic line is maintained by maternal transmission. This PWS mouse model will be used to determine which genes play which roles in PWS, and to define the biochemical basis of the disorder. The main hypotheses are that PWS is a contiguous gene syndrome with multiple imprinted genes contributing to the PWS phenotype, and that these genes can be uniquely identified by transgenic rescue of the PWS mouse model. The goal of this proposal is to genetically dissect the imprinted gene(s) underlying each component of the PWS and PWS mouse model phenotypes by an approach consisting of three Specific Aims: (1) use of transgenic rescue of the PWS-associated phenotypes in the PWS mouse model, in order to define specific genes for each phenotypic component. Transgenic technology utilizing genomic clones of varying gene content from the 2 Mb PWS region, and cDNA clones, will be done to rescue the PWS-related phenotypes; (2) to characterize the function of genes shown to be responsible for phenotypic aspects of PWS; and (3) to screen PWS or PWS-like patients with no known 15q11-q13 molecular abnormality, or those patients with single phenotypic components of PWS, for mutations in each candidate gene for specific phenotypic components identified by mouse models.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD031491-08
Application #
6387644
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Oster-Granite, Mary Lou
Project Start
1994-01-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
8
Fiscal Year
2001
Total Cost
$308,767
Indirect Cost
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Miller, Jennifer; Kranzler, John; Liu, Yijun et al. (2006) Neurocognitive findings in Prader-Willi syndrome and early-onset morbid obesity. J Pediatr 149:192-8
Stefan, M; Ji, H; Simmons, R A et al. (2005) Hormonal and metabolic defects in a prader-willi syndrome mouse model with neonatal failure to thrive. Endocrinology 146:4377-85
Stefan, Mihaela; Claiborn, Kathryn C; Stasiek, Edyta et al. (2005) Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes. BMC Genomics 6:157
Stefan, Mihaela; Portis, Toni; Longnecker, Richard et al. (2005) A nonimprinted Prader-Willi Syndrome (PWS)-region gene regulates a different chromosomal domain in trans but the imprinted pws loci do not alter genome-wide mRNA levels. Genomics 85:630-40
Shapira, Nathan A; Lessig, Mary C; Lewis, Mark H et al. (2004) Effects of topiramate in adults with Prader-Willi syndrome. Am J Ment Retard 109:301-9
Nicholls, Robert D; Gray, Todd A (2004) Cellular source of the poxviral N1R/p28 gene family. Virus Genes 29:359-64
Stefan, Mihaela; Nicholls, Robert D (2004) What have rare genetic syndromes taught us about the pathophysiology of the common forms of obesity? Curr Diab Rep 4:143-50
Rainier, Shirley; Chai, Jing-Hua; Tokarz, Debra et al. (2003) NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet 73:967-71
Chai, J-H; Locke, D P; Greally, J M et al. (2003) Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet 73:898-925
Ge, Yin- Lin; Ohta, Tohru; Driscoll, Daniel J et al. (2002) Anorexigenic melanocortin signaling in the hypothalamus is augmented in association with failure-to-thrive in a transgenic mouse model for Prader-Willi syndrome. Brain Res 957:42-5

Showing the most recent 10 out of 44 publications