• fragile X syndrome

Fragile X mental retardation syndrome (FXS or FRAX) is one of several syndromes caused by mutation in the FMR1 gene, which encodes a component of an RNA-binding complex that binds to the mRNA cap and mediates translational repression. The causative genetic lesion of FXS is usually a trinucleotide (CGG)n repeat expansion within the 5' UTR of the FMR1 mRNA of >200 CGG repeats. FMR1 alleles with >200 CGG repeats undergo epigenetic silencing early in development, resulting in undetectable levels of mRNA and FMR1 protein in affected males. Smaller loss-of-function lesions in the FMR1 gene have also been implicated in FXS. See the human disease reports for fragile X syndromes (FBhh0000123) and fragile X tremor/ataxia syndrome (FBhh0000137) for additional information about fragile X models in flies.

There is a single fly ortholog of FMR1, Dmel\Fmr1, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\Fmr1 is also orthologous to two additional human genes, FXR1 and FXR2.

Multiple different UAS constructs of the human gene Hsap\FMR1 have been introduced into flies, including wild-type. Heterologous rescue (functional complementation) has been demonstrated: a wild-type UAS-FMR1 construct rescues neuronal and non-neuronal phenotypes of a Dmel\Fmr1 loss-of-function allele. Phosphomimetic and dephosphomimetic variants affecting a phosphorylation site thought to control FMR1 RNA-binding have also been created and tested in flies; the phosphomimetic variant rescues tested phenotypes of a Dmel\Fmr1 amorphic allele. The orthologous human genes Hsap\FXR1 and Hsap\FXR2 have also been introduced into flies; expression of either of these two genes rescues the non-neuronal phenotypes of a Dmel\Fmr1 loss-of-function allele, but fails to rescue the neuronal phenotypes.

Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R140Q in the fly Fmr1 gene (corresponds to R138Q in the human FMR1 gene); I307N in the fly Fmr1 gene (corresponds to I304N in the human FMR1 gene).

Most amorphic mutations of Dmel\Fmr1 are semi-lethal, with the majority of animals dying during the pupal stage; effects can be studied in larvae and in surviving adults. Adults exhibit neurological phenotypes such as memory defective, locomotor rhythm defective, courtship behavior defective, and neuroanatomy defective; males sterility or semi-sterility is observed for several alleles; sleep and circadian defects have been observed. Extensive physical and genetic interactions of Dmel\Fmr1 have been described; see below and in the gene report for Fmr1.

The Drosophila microRNA mir-219 has been shown to regulate Fmr1 levels via binding sites in the Fmr1 mRNA 3' UTR. Larvae overexpressing mir-219 exhibit morphological abnormalities at the neuromuscular junction.

Symptoms overlapping those of autism spectrum disorder (FBhh0000514) are frequently observed in individuals with fragile X syndrome; this aspect of FXS has also been investigated in flies using Fmr1. RNAi-effected loss of function leads to reduced behavioral flexibility as shown by severe reversal-learning impairment; it is postulated that this phenotype results from the failure to properly activate Rac1-dependent forgetting.

A fly model investigating insulin misregulation in Fmr1 mutant animals has been developed ('insulin pathway effects, FMR1-related' FBhh0000957). Expression of Dmel\Fmr1 in the insulin-producing cells (IPCs) of the brain is sufficient to restore normal circadian behavior and to rescue the memory deficit phenotype of animals carrying loss-of-function Fmr1 mutations.

[updated Mar. 2019 by FlyBase; FBrf0222196]