FRAGILE X RELATED GENES IN MENTAL RETARDATION

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

Fragile X syndrome (MIM number 30955) is among the most common human single gene disorders, and is the leading cause of inherited mental retardation, with an estimated frequency of 1/2000-1/4000 individuals world-wide. The gene defective in fragile X syndrome (FMR1) was identified by positional cloning in 1991, yet its function, and the consequences of its absence remain unknown. The FMR1 protein interacts with mRNAs in a variety of cell types, and has been shown to associate with ribosomes. These apparently fundamental properties are difficult to reconcile with the relatively mild phenotype found in fragile X patients and in a mouse knockout of the Fmr1 gene. The central hypothesis of the project proposed here is that two FMR1-related proteins, FXR1 and FXR2 provide redundancy of function for FMR1. This redundancy masks the phenotypic consequences of loss of function mutations in humans and mice that would allow better definition of the function of FMR1. In order to test this hypothesis, mutations in the Fxr1 and Fxr2 genes are proposed. These will be introduced into the mouse genome with the capability to provide conditional knockouts using the site specific recombinase Cre derived from phage P1, which recognizes lox P sites for recombination. Mutant mice will be analyzed by biochemical, histological and behavioral methods in order to determine the consequences of the absence of one or more of these genes. Conditional mutations will be created to investigate tissue specific or developmental timing effects of gene ablation. Mutations in the Fxr1 and Fxr2 proteins, especially in combination with Fmr1 mutations, should provide resolution of the redundancy question. Such mutations and combinations of mutations will also provide important evidence for the functions of these genes. Results from this project will provide additional data regarding the normal function of FMR1 and the consequences of its absence in fragile X syndrome. These data will allow further investigation of potential therapeutic intervention in this common form of mental retardation.