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Fragile X syndrome, the most frequent form of hereditary mental retardation, is due to a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Like fragile X patients, FMR1-knockout (FMR1-KO) mice lack the normal fragile X mental retardation protein (FMRP) and show both cognitive alterations and an immature neuronal morphology. We reared FMR1-KO mice in a C57BL/6 background in enriched environmental conditions to examine the possibility that experience-dependent stimulation alleviates their behavioral and neuronal abnormalities. FMR1-KO mice kept in standard cages were hyperactive, displayed an altered pattern of open field exploration, and did not show habituation. Quantitative morphological analyses revealed a reduction in basal dendrite length and branching together with more immature-appearing spines along apical dendrites of layer five pyramidal neurons in the visual cortex. Enrichment largely rescued these behavioral and neuronal abnormalities while increasing [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit 1 (GluR1) levels in both genotypes. Enrichment did not, however, affect FMRP levels in the WT mice. These data suggest that FMRP-independent pathways activating glutamatergic signaling are preserved in FMR1-KO mice and that they can be elicited by environmental stimulation. fragile X mental retardation protein | mental retardation | FMR1 gene | AMPA receptor | dendritic spines

Cytosine methylation is an epigenetic mechanism in eukaryotes that is often associated with stable transcriptional silencing, such as in X-chromosome inactivation and genomic imprinting. Aberrant methylation patterns occur in several inherited human diseases and in many cancers. To understand how methylated and unmethylated states of cytosine residues are transmitted during DNA replication, we develop a population-epigenetic model of DNA methylation dynamics. The model is informed by our observation that de novo methylation can occur on the daughter strand while leaving the opposing cytosine unmethylated, as revealed by the patterns of methylation on the two complementary strands of individual DNA molecules. Under our model, we can infer site-specific rates of both maintenance and de novo methylation, values that determine the fidelity of methylation inheritance, from double-stranded methylation data. This approach can be used for populations of cells obtained from individuals without the need for cell culture. We use our method to infer cytosine methylation rates at several sites within the promoter of the human gene FMR1. bisulfite genomic sequencing | epigenetic fidelity | fragile X syndrome | mathematical modeling | population epigenetics

A study demonstrated that the association of Fragile-X mental retardation protein (FMRP) with brain polyribosomes was abrogated by competition with the MRP kissing complex RNA, but not by high-affinity G-quartet RNAs. It was concluded that mental retardation associated with the 1304N mutation, and likely, the Fragile-X syndrome might relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation.

Fragile X syndrome results from the transcriptional silencing of a gene, Fmr1, that codes for an mRNA-binding protein (fragile X mental retardation protein, FMRP) present in neuronal dendrites. FMRP can act as a translational suppressor, and its own translation in dendrites is regulated by group I metabotropic glutamate receptors (mGluRs). Multiple lines of evidence suggest that mGluR-induced translation is exaggerated in Fragile X syndrome because of a lack of translational inhibition normally provided by FMRP. We characterized the role of FMRP in the regulation of mRNA granules, which sediment as a heavy peak after polysomes on sucrose gradients. In WT mouse brain, FMRP distributed with polysomes and granules. EM and biochemical analyses suggested that the granule fraction itself contained clusters of polysomes. In Fmr1 knockout brain, we observed a significant decrease in the amount of mRNA granules relative to WT mice. This difference appeared to be due to a role of FMRP in regulating the activation of granules during mGluR-induced translation; in vivo administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine increased granule content in Fmr1 knockout mouse brain to levels comparable with those seen in WT brain. In accord with a role of mGluR5 in the regulation of ongoing translation in vivo, we observed that the phosphorylation of several initiation factors in response to application of the mGluR1/5 agonist S-3,5-dihydroxyphenylglycine in vitro was blocked by methyl-6-(phenylethynyl)pyridine. Together, these data suggest that although large, polysome-containing granules can form in the absence of FMRP, their use in response to mGluR-induced translation is exaggerated. fragile X syndrome | translation | 2-methyl-6-(phenylethynyl)pyridine

Fragile X syndrome is caused by the absence of the fragile X mental retardation protein (FMRP). This RNA-binding protein is widely expressed in human and mouse tissues, and it is particularly abundant in the brain because of its high expression in neurons, where it localizes in the cell body and in granules throughout dendrites. Although FMRP is thought to regulate trafficking of repressed mRNA complexes and to influence local protein synthesis in synapses, it is not known whether it has additional functions in the control of translation in the cell body. Here, we have used recently developed approaches to investigate whether FMRP is associated with the translation apparatus. We demonstrate that, in the brain, FMRP is present in actively translating polyribosomes, and we show that this association is acutely sensitive to the type of detergent required to release polyribosomes from membranous structures. In addition, proteomic analyses of purified brain polyribosomes reveal the presence of several RNA-binding proteins that, similarly to FMRP, have been previously localized in neuronal granules. Our findings highlight the complex roles of FMRP both in actively translating polyribosomes and in repressed trafficking ribonucleoparticle granules.

Fragile X syndrome (fraX) is the most common known cause of inherited developmental disability, fraX is associated with a CGG expansion in the FMR1 gene on the long arm of the X chromosome. Behavioral deficits, including problems with impulse control and distractibility, are common in fraX. We used functional brain imaging with a Go/NoGo task to examine the neural substrates of response inhibition in females with fraX (ages 10-22) and age- and gender-matched typically developing subjects. Although subjects with fraX had significantly lower IQ scores, as a group their performance on the Go/NoGo task was equivalent to that of the typically developing group. However, females with fraX showed abnormal activation patterns in several cortical and subcortical regions, with significantly reduced activation in the supplementary motor area, anterior cingulate and midcingulate cortex, basal ganglia, and hippocampus. An important finding of our study is that neural responses in the right ventrolateral prefrontal cortex (PFC) and the left and right striatum were correlated with the level of FMR1 gene expression. Our findings support the hypothesis that frontostriatal regions typically associated with response inhibition are dysfunctional in females with fraX. In addition to task-related activation deficits, reduced levels of 'deactivation' were observed in the ventromedial PFC, and, furthermore, these reductions were correlated with the level of FMR1 gene expression. The ventromedial PFC is a key node in a 'default mode' network that monitors mental and physiological states; we suggest that self-monitoring processes may be aberrant in fraX. genetic | Go/NoGo | response inhibition | prefrontal cortex | basal ganglia

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.

In humans, failure to express the fragile X mental retardation protein (FMRP) gives rise to fragile X syndrome, the most common form of inherited mental retardation. A fragile X knockout (fmr1 KO) mouse has been described that has some of the characteristics of patients with fragile X syndrome, including immature dendritic spines and subtle behavioral deficits. In our behavioral studies, fmr1 KO mice exhibited hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Our finding of impaired performance of fmr1 KO mice on a passive avoidance task is suggestive of a deficit in learning and memory. In an effort to understand what brain regions are involved in the behavioral abnormalities, we applied the [[sup.14]C]deoxyglucose method for the determination of cerebral metabolic rates for glucose (CM[R.sub.glc]). We measured CM[R.sub.glc] in 38 regions in adult male fmr1 KO and WT littermates. We found CM[R.sub.glc] was higher in all 38 regions in fmr1 KO mice, and in 26 of the regions, differences were statistically significant. Differences in CM[R.sub.glc] ranged from 12% to 46%, and the greatest differences occurred in regions of the limbic system and primary sensory and posterior parietal cortical areas. Regions most affected are consistent with behavioral deficiencies and regions in which FMRP expression is highest. Higher CM[R.sub.glc] in fragile X mice may be a function of abnormalities found in dendritic spines.

This review discusses genetics and molecular aspects of the fragile X syndrome, which represents one of the common forms of inherited mental retardation.

Byline: E. Yu. Siyanova (1), S. M. Mirkin (1) Keywords: trinucleotide repeat; expansion; replication; recombination; gene expression; genome instability; genome polymorphism; non-Mendelian inheritance; genetic anticipation Abstract: This review describes a novel type of genome instability, expansion of trinucleotide repeats. Originally discovered in 1991 upon cloning the gene responsible for the fragile X syndrome, it has proved to be a general phenomenon responsible for a growing number of human neurological disorders. Besides apparent medical importance, the discovery of trinucleotide repeat expansion unraveled a fundamental problem of human genetics: a non-Mendelian type of inheritance called anticipation. Understanding the mechanisms of repeat expansion and the molecular pathways leading from these expansions to human diseases became a formidable task for modern biology and one of its spectacular achievements. Here we discuss the major breakthroughs in this field made during the last decade, with an emphasis on molecular models of repeat expansion. Author Affiliation: (1) Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA Article History: Registration Date: 08/10/2004

A study of single sperm from four fragile-X premutation males is discussed. The study has shown that the FMR1 CGG repeat is far more unstable in the germline than in somatic cells. Also cis or trans factors may have additional influence on repeat instability. The repeats in sperm from the 75- and 78-repeat males had quite different ranges of size and AGG interruption in their somatic cells.

Fragile sites involve both cytogenetic similarity and molecular diversity. Some common fragile sites may affect gene expression, setting up local regions of instability. Understanding mechanisms of the instability and the biological significance is a challenge. Just three of the various classes of rare fragile sites have been studied from the molecular perspective and more is known about the folate-sensitive ones than others. Fragile sites are classified with some cytogenetic and molecular properties.

Byline: Carl Feinstein (1), Allan L. Reiss (1) Keywords: Fragile X syndrome; autism; behavioral phenotype; cognitive phenotype; behavioral neurogenetics Abstract: The relationship between the fragile X syndrome (FXS) and autism is reviewed. Shortly after the FXS was first described, it was noted that certain behaviors commonly found in afflicted individuals resemble certain features of autism. Research concerning a possible relationship between these conditions is summarized. The outcome of this research indicates that FXS is not a common cause of autism, although the number of individuals with FXS who meet diagnostic criteria for autism is higher than can be accounted for by chance. The major focus of this paper highlights that FXS is a well-defined neurogenetic disease that includes a cognitive behavioral phenotype, and has both a known biological cause and an increasing well-delineated pathogenesis. Autism is a behaviorally defined syndrome whose syndromic boundaries and biological causes are not known. These profound differences complicate comparisons and causal discussions. However, the behavioral neurogenetic information available about FXS suggests certain pathways for future research directed at elucidating the syndrome of autism. Author Affiliation: (1) Division of Child and Adolescent Psychiatry and Child Development, Stanford University School of Medicine, Stanford, California, 94305-5719 Article History: Registration Date: 29/09/2004

Selection against sperm with full mutations appears to account for the difference between female and male transmission of the FMR1 CGG repeat associated with fragile X syndrome. Inheritance of the full mutation is equally likely for male and female offspring. The risk of full-mutation offspring is positively correlated with premutation-female repeat size, and the daughter's repeat size is also positively correlated with premutation-male repeat size.

Primary X-linked metal retardation (MRX) is a heterogeneous condition with affected patients having no distinctive clinical features in common except cognitive impairment. Many genetic defects linked to MRX can involve ten different genes. A new gene on the long arm of the X-chromosome has been characterized and identified in unrelated individuals of mutations predicted to cause loss of function. It is highly expressed in fetal brain, encoding a ologophrenin-1 protein containing a Rho-GTPase-activating protein domain. This demonstrates a link between cognitive impairment and defective signalling pathways that rely on Ras-like GTPase.