MOLECULAR STUDIES OF GENOMIC IMPRINTING IN HUMANS

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DESCRIPTION: (Adapted from investigator's abstract) 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.