Fragile X syndrome is the most common inherited form of mental retardation. It is caused by loss of FMR1 gene activity due
to either lack of expression or expression of a mutant form of the protein. In mammals, FMR1 is a member of a small protein
family that consists of FMR1, FXR1, and FXR2. All three members bind RNA and contain sequence motifs that are
commonly found in RNA-binding proteins, including two KH domains and an RGG box. The FMR1/FXR proteins also
contain a 60S ribosomal subunit interaction domain and a protein-protein interaction domain which mediates homomer and
heteromer formation with each family member. Nevertheless, the specific molecular functions of FMR1/FXR proteins are
unknown. Lili Wan, et al 2000 reported the characterization of dFMR1, a Drosophila melanogaster
Homolog of the Fragile X Mental Retardation Protein.
They report the cloning and characterization of a Drosophila melanogaster homolog of the mammalian
FMR1/FXR gene family. This first invertebrate homolog, termed dfmr1, has a high degree of amino acid sequence
identity/similarity with the defined functional domains of the FMR1/FXR proteins. The dfmr1 product binds RNA and is
similar in subcellular localization and embryonic expression pattern to the mammalian FMR1/FXR proteins. Overexpression
of dfmr1 driven by the UAS-GAL4 system leads to apoptotic cell loss in all adult Drosophila tissues examined. This
phenotype is dependent on the activity of the KH domains. The ability to induce a dominant phenotype by overexpressing
dfmr1 opens the possibility of using genetic approaches in Drosophila to identify the pathways in which the FMR1/FXR
proteins function.
General function
RNA metabolism, RNA processing
Comment
Fragile X syndrome is the most common form of hereditary mental retardation whose effects
are traced to the loss of function of a single gene, named FMR1. This syndrome affects
approximately 1 in 5,000 male births and is globally distributed throughout the human
population . In most cases, the disease results from the repression of FMR1 gene expression that is due to an expansion of a CGG trinucleotide repeat in the 5' untranslated
region of the gene . Subsequent methylation of this expanded repeat results in transcriptional silencing of the FMR1 gene . A few fragile X patients with partial or complete deletions of the FMR1 gene have been identified, and these patients have phenotypes similar to those affected by the
trinucleotide repeat expansion. One patient who has a single point mutation in the FMR1 gene that replaces an
isoleucine residue at amino acid 304 with asparagine (I304N) exhibits a particularly severe fragile X phenotype .