The triplet repeat diseases, currently seven in number, represent a new mutational class that has not previously been identified as a basis of genetic change in any of the """"""""model"""""""" organisms. Fragile-X syndrome, the most common form of inherited mental retardation, was the first of these diseases for which publication demonstrated that the expansion of a triplet repeat was correlated with the disease state. Fragile-X syndrome also exhibits another unusual phenomenon in which gene inactivation occurs in a parent-specific manner: mutant alleles of the FMR1 gene are often inactivated by hypermethylation of a 5' CpG island when it is inherited from the mother but not from the father. The inactive state of the mutant FMR1 gene is described here as """"""""imprinted"""""""" because of this pattern of inheritance. The long-term objectives of the proposed research are to understand genetic and epigenetic principles of the fragile-X syndrome. Specific questions concern the molecular basis of the instability of the CGG repeat within the candidate gene for the fragile-X syndrome, FMR1; the molecular nature of the imprinted or inactive state of the fragile-X mutation; whether or not the inactive state is reversible; the relationship between the cytogenetic expression of the fragile site at Xq27.3 (FRAXA), the expanded, hypermethylated CGG repeat, and delayed replication FMR1. The research design and methods for achieving these goals involve a combination of genetic and molecular approaches: molecular tests will assess the timing of DNA replication; methylation patterns at the fragile- X site will be characterized by restriction endonuclease assays and direct genomic sequencing; 5-azacytidine treatment of cell cultures will be used to assess the reversibility of the imprinted state. The health relatedness of this project concerns the genetic, epigenetic, and molecular basis of the fragile-X syndrome. The principles learned from this study also may be useful in understanding other diseases that involve expansion of triplet repeats: Kennedy disease, myotonic dystrophy, Huntington disease, spinocerebellar ataxia type I, dentatorubral- pallidoluysian atrophy, and FRAXE-related mental retardation. There is also potential relevance to disorders that involve either abnormal or normal genomic imprinting, such as Prader-Willi and Angelman syndromes, rhabdomyosarcoma, Beckwith-Wiedemann syndrome, and Wilms tumor.
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