Pathogenic consequences of expansions and deletions of CGG repeats in the FMR1 gene

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

The FMR1 gene encodes fragile X mental retardation protein (FMRP), which regulates translation of specific target RNAs. Normally the FMR1 gene contains 6-54 CGG repeats in the 5'UTR. Intermediate expansion of CGG repeats (55-200), referred to as premutation, results in reduced translation of FMR1 RNA associated with a neurodegenerative disorder called fragile X tremor ataxia (FXTAS) and a reproductive disorder called fragile X premature ovarian insufficiency (FXPOI). Larger expansion of CGG repeats (>200), referred to as full mutation, results in methylation and transcriptional silencing of the FMR1 gene associated with a neurodevelopmental disorder called fragile X syndrome (FXS). Deletions of CGG repeats in the FMR1 gene, are often associated with FXS or FXTAS. However the pathogenic consequences of such deletions has not been investigated. Here we will determine if CGG repeat deletions in FMR1 affect: localization of FMR1 RNA in granules, bursty translation of FMRP at synapses, and synthesis of poly-arginine FMRP by repeat associated nonAUG (RAN) translation and whether any of these phenomena affect translation of specific FMRP target RNAs. The results may identify a new pathogenic mechanism for deletion of CGG repeats in FMR1 and may also have important consequences for therapeutic strategies involving deletion of repeats in FXS, FXTAS and FXPOI, or in other trinucleotide repeat disorders.