New insights into fragile X syndrome: from molecules to neurobehaviors

Abstract

Fragile X syndrome -a common form of inherited mental retardation -is caused by the loss of the fragile X mental retardation 1 protein (FMRP). FMRP is an RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with translating polyribosomes. It has been proposed that FMRP is involved in synaptic plasticity through the regulation of mRNA transportation and translation. Recent advances in the identification of the mRNA ligands that are bound by FMRP, the RNA sequence and structure required for FMRP -RNA interaction, and the physiological consequences of FMRP deficiency in the brain are important steps towards understanding the molecular pathogenesis of fragile X syndrome, and learning and memory in general.Fragile X syndrome is the most common form of inherited mental retardation, with the estimated prevalence of one in 4000 males and one in 8000 females. In addition to cognitive deficits, the phenotype of fragile X syndrome includes mildly abnormal facial features (a prominent jaw, high forehead and large ears), MACROORCHIDISM (see Glossary) in postpubescent males and subtle connective tissue abnormalities [1]. Many patients also manifest attention-deficit hyperactivity disorder and autistic-like behavior. As one of the first identified human disorders caused by trinucleotide repeat expansion, fragile X syndrome is the result of a massive CGG trinucleotide repeat expansion within the gene fragile X mental retardation 1 (FMR1). FMR1 is a highly conserved gene that consists of 17 exons, and spans , 38 kilobases (kb). Within the 4.4-kb FMR1 transcript, a CGG trinucleotide repeat is located in the 5 0 untranslated region (UTR) [2]. Among normal individuals, this CGG repeat is highly polymorphic in length and content, often punctuated by AGG interruptions. The normal repeat size ranges from 7 to , 54, with 30 repeats found in the most common allele. In most affected individuals, CGG repeats are massively expanded over 230 repeats (full mutation) and become abnormally hypermethylated, which results in the transcriptional silencing of FMR1 [1]. Identification of other mutations in FMR1 (e.g. deletions and a point mutation among patients with the typical phenotype, but without FRAGILE SITE expression) has confirmed that the FMR1 gene is the only gene involved in the pathogenesis of fragile X syndrome and the loss of FMR1 product -fragile X mental retardation protein (FMRP) -causes fragile X syndrome [1]. A mouse model of fragile X syndrome was created using gene targeting; the Fmr1-knockout mice exhibit macroorchidism and subtle deficits in learning and memory, which mimic the human phenotype [3].In this review, we discuss the recent progress in understanding the biological functions of FMRP and the physiological consequences of its absence that lead to mental retardation. Features of FMRPFMRP is widely expressed in fetal and adult tissues, with the most abundant expression in brain and testes [4]. FMRP, and its autosomal paralogs the fragile-X-related protein FXR1P and FXR2P, consist...

Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice

“…37 For example, FMR1 and the fragile X-related genes, FXR1 and FXR2, encode a family of functionally similar RNA-binding proteins. 38 Although FXR1 and FXR2 expression levels are not altered in FXS patients or Fmr1-KO mice, 39,40 greater redundancy among these proteins in mice may attenuate the impact of the FMR1 mutation. In this regard, it is of particular interest that PPI is disrupted in Fxr2-KO mice, and learning is more severely affected in these mice compared to Fmr1-KO mice.…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…The proposed mechanism of action of FMRP has been based on a combination of findings (Figure 2;Jin and Warren, 2003). Cytoplasmic FMRP is dimerized and transported into the nucleus via its nuclear localization signal.…”

Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

“…As a result of this expansion, the product of the FMR1 gene, fragile X mental retardation protein (FMRP), is not expressed (Oberle et al, 1991;Verkerk et al, 1991;Kooy, 2003). FMRP is an mRNA binding protein that is associated with polyribosomes and is thought to be involved in the translational efficiency and/or trafficking of certain mRNAs (Jin and Warren, 2003;Willemsen et al, 2004).…”