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Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins

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Science  17 Aug 2018:
Vol. 361, Issue 6403, pp. 709-712
DOI: 10.1126/science.aas9963

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Fragile X and fragile translation in flies

Mutations in the fragile X mental retardation 1 (FMR1) gene underlie fragile X syndrome and fragile X–associated primary ovarian insufficiency, which are prominent intellectual disability and reproductive disorders, respectively. FMR1 is thought to reduce protein synthesis (translation) at synapses. In Drosophila oocytes, Greenblatt and Spradling found that Fmr1 loss leads to oocytes that generate embryos exhibiting neural defects (see the Perspective by Aryal and Klann). Ribosome profiling of oocytes identified a specific role for FMR1 in enhancing the translation of large proteins, including many associated with autism. FMR1 seems to help maintain translation of large mRNAs that otherwise condense into inactive ribonucleoprotein particles. This mechanism may underlie other causes of autism and mental dysfunction.

Science, this issue p. 709; see also p. 648

Abstract

Mutations in the fragile X mental retardation 1 gene (FMR1) cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.

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