This new proposal outlines a series of complementation experiments of a mouse model of Prader-Willi syndrome, which was previously constructed by the investigator. The clinically distinct genetic disorders Prader-Willi (PWS) and Angelman (AS) syndromes arise from opposite patterns of genomic imprinting of human chromosome 15q11-q13. PWS results from loss of paternal gene expression, and AS results from a loss of maternal gene expression. This proposal is based on the finding that while there is a class of human AS patients, which have point mutations in a single causative gene, a similar class of PWS patients has not been identified. This suggests that PWS is a contiguous gene syndrome, caused by the lack of expression of two or more imprinted genes. Individual knock-out mutations created in each of the four genes identified, as candidates for PWS have not revealed a phenotype in mice. The investigator has recently created a deletion mutation involving a global regulatory element, called the Imprinting Center, and produced a mouse model for PWS. In this model, all four of the PWS candidate genes are silenced. The first specific aim is to take advantage of this mouse model to test the hypothesis that two or more genes are responsible for PWS. The strategy will be to determine which combination of the candidate genes when expressed as transgenes are able to complement the PWS mouse model. The second specific aim is to extend this complementation assay to investigate the anatomical sites of the various PWS clinical features by using tissue-restricted expression of the complementing transgene(s).

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD037872-01
Application #
2884429
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Oster-Granite, Mary Lou
Project Start
1999-08-17
Project End
2004-07-31
Budget Start
1999-08-17
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Rodriguez-Jato, Sara; Shan, Jixiu; Khadake, Jyoti et al. (2013) Regulatory elements associated with paternally-expressed genes in the imprinted murine Angelman/Prader-Willi syndrome domain. PLoS One 8:e52390
DuBose, Amanda J; Smith, Emily Y; Johnstone, Karen A et al. (2012) Temporal and developmental requirements for the Prader-Willi imprinting center. Proc Natl Acad Sci U S A 109:3446-50
Smith, Emily Y; Futtner, Christopher R; Chamberlain, Stormy J et al. (2011) Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. PLoS Genet 7:e1002422
Dubose, Amanda J; Smith, Emily Y; Yang, Thomas P et al. (2011) A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center. Hum Mol Genet 20:3461-6
DuBose, Amanda J; Johnstone, Karen A; Smith, Emily Y et al. (2010) Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-IC. Neurogenetics 11:145-51
Leung, Karen N; Vallero, Roxanne O; DuBose, Amanda J et al. (2009) Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size. Hum Mol Genet 18:4227-38
Johnstone, Karen A; DuBose, Amanda J; Futtner, Christopher R et al. (2006) A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Hum Mol Genet 15:393-404
Chamberlain, Stormy J; Johnstone, Karen A; DuBose, Amanda J et al. (2004) Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice. Hum Mol Genet 13:2971-7