Review
Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes

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Abstract

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene that lead to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. The recent observations of unexpected phenotypes in some carriers of fragile X premutations suggest a pathological role, in these individuals, of an abnormal FMR1 mRNA. FMRP was recently shown to interact preferentially with mRNAs containing a G quartet structure. Mouse and Drosophila models are used to decipher the function of FMRP, which was found to inhibit translation of some mRNA targets, but may be stimulatory in other cases. Proteins interacting with FMRP have been identified, and suggest a link with the Rac1 GTPase pathway that is important in neuronal maturation. Recent advances also include identification of other genes implicated in X-linked mental retardation.

Introduction

Mutations in X-linked genes account, at least in part, for the excess of males in schools and institutions for mentally handicapped (reviewed in [1]). In recent years, many genes have been identified that are indeed implicated in syndromic forms of X-linked mental retardation (XLMR; forms characterized by specific clinical symptoms) or in ‘non specific’ (or non syndromic) XLMR. The latter is characterized by extensive non-allelic genetic heterogeneity, as 12 genes have been already found mutated in families with non specific XLMR and linkage analysis suggests that the total number of such genes may reach 30–50 [2]. Several of the identified genes code for proteins that function in the Rho/Rac GTPase signaling pathway that is implicated in neuronal maturation [2].

The most frequent form of XLMR is the fragile X mental retardation syndrome, caused by an unstable expansion of the CGG repeat within the FMR1 gene, which leads to transcriptional shut off and loss of expression of the FMRP, an RNA-binding protein. Since 1991, extensive work has been devoted to analysis of the mutation mechanisms, and to an understanding of FMRP function (see 3., 4., 5.). In this review, we focus on FMRP function, with an emphasis on the recent significant advances addressing the following questions: does FMRP bind to specific sets of mRNAs and what is the effect of this binding on metabolism and translation of such target mRNAs; what are the protein partners of FMRP that may modulate its functions; what are the mechanisms underlying the effect of FMRP deficiency on cognitive functions; what are the functional differences between FMRP and its close homologs FXR1P and FXR2P? We also discuss recent observations that premutation, the intermediate form of the fragile X CGG expansion, is associated in some carriers with phenotypes—premature ovarian failure in females, late-onset movement disorder in males—that are unlikely to result from FMRP deficiency, and suggest an effect of the presence of an abnormal FMR1 mRNA. We briefly update the status of identified XLMR genes since publication of a recent review [2], and notably the discovery of a homeobox gene, the Aristaless homolog ARX, as mutated in many families with syndromic or non-syndromic forms of XLMR.

Section snippets

Key facts on fragile X syndrome and FMRP

The fragile X mental retardation syndrome is the most common monogenic form of mental retardation, affecting ∼1 in 4000 males, and on average less severely, 1 in 7000 females (see [6] for a review). In addition to the cognitive deficits, affected boys often manifest a hyperactive and/or autistic-like behavior. Physical signs in males frequently include evocative facial features, post pubertal macroorchidism, and minor signs of connective tissue dysplasia [7]. The disease is caused by an

Unexpected phenotypes in premutation carriers

The premutation was initially thought to have either little or no effect on FMR1 expression, and thus to have no associated phenotypic manifestations. It had been reported, however, that FMR1 mRNA transcribed from a premutated gene, and that carries the moderate CGG expansion, is less efficiently translated [25]. This appeared somewhat in contradiction with the observation that rare males with unmethylated large expansions have a normal intelligence, indicative of the expression of functional

Mutation mechanisms

In the years following the discovery of the CGG repeat mutation, many papers analyzed the phenomenology of the various states of the expansion, its multistep evolution in human populations, and the stabilizing role of AGG interruptions in the CGG repeat (see [3] for review). More mechanistic analyses of triplet repeat instability have been performed in simpler bacterial or yeast systems (more often on CTG/CAG repeats than on CGG repeats). Analysis in mammalian systems has been impaired by the

mRNAs interacting with FMRP and translational regulation

Several laboratories have recently focused their attention on the identification of mRNAs that can specifically bind to FMRP. An early study had reported that FMRP binds 4% of brain mRNAs [46], but the identity of these mRNAs had remained elusive. The fact that FMRP manifests non-specific RNA binding, as shown by its ability to bind to polyU and polyG, certainly hindered identification of specific mRNA targets. The mRNA of FMR1 itself had, however, been found to bind to FMRP, and to be present

FMRP-interacting proteins

Another approach towards an understanding of FMRP function has been the search for proteins that interact directly with FMRP or that are components of the FMRP-containing mRNP complex (48., 57.). Several proteins have been characterized to date, as follows.

First, FXR1P and FXR2P are close homologs of FMRP and are able to both homo- and heterodimerize with it [58]. The two proteins contain the same functional motifs as FMRP and are supposed to have similar functions. Although the three proteins

Physiological function of FMRP in the brain

The Fmr1 knockout mouse has been used intensively to study FMRP function in brain. This model presents rather subtle differences in behavior and spatial learning compared to wild-type mice that are subject to strain background effects 24., 69., 70., 71.. Using various experimental paradigms, the Fmr1 knockout mouse has been reported to show increased sensitivity to audiogenic epileptic seizures 72., 73., and greater response to low-intensity auditory stimuli 73., 74., whereas abnormal responses

Newly identified XLMR genes

The field of X-linked mental retardation has been thoroughly described in a book [1], and advances in the identification and functional characterization of XLMR genes have been reviewed recently [2]. We here briefly update on novel findings in this fast-moving field.

The most significant result is certainly the discovery of a homeobox gene, the Aristaless homolog ARX, as mutated in 20 families with either syndromic forms of XLMR: with infantile spasms, called ISSX (MIM 308350) or with dystonic

Conclusions

Important progress has been made in the past year, notably concerning the specificity of interaction of FMRP with some mRNAs. Lists of potential mRNA targets are now available, but they must be validated using other functional approaches—as was done in a single case in Drosophila, to reveal how FMRP interaction with specific mRNAs affects their expression. Several lines of evidence suggest that FMRP may modulate synaptogenesis through an action on cytoskeletal proteins, by interaction with

Acknowledgements

We wish to thank our colleagues A Schenck, H Moine, C Schaeffer, A Giangrande, for fruitful collaboration and discussion and S Metz for help. Research on FMRP in the authors laboratory is supported by the National Institutes of Health, HFSP (Human Frontiers Science Program, Université Louis Pasteur, and by general grants from INSERM, CNRS, Institut Universitaire de France and CHRU (Centre Hospitalier Régional Universitaire). B Bardoni was supported by FRAXA foundation.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (93)

  • D. Wohrle et al.

    Demethylation reactivation, and destabilization of human fragile X full-mutation alleles in mouse embryocarcinoma cells

    Am J Hum Genet

    (2001)
  • S.L. Nolin et al.

    FMR1 CGG-repeat instability in single sperm and lymphocytes of fragile-X premutation males

    Am J Hum Genet

    (1999)
  • V. Brown et al.

    Purified recombinant Fmrp exhibits selective RNA binding as an intrinsic property of the fragile X mental retardation protein

    J Biol Chem

    (1998)
  • Y.-J. Sung et al.

    RNAs that interact with the fragile-X syndrome RNA binding protein FMRP

    Biochem Biophys Res Commun

    (2000)
  • Y.Q. Zhang et al.

    Drosophila Fragile X-related gene regulates MAP1B homolog Futsch to control synaptic structure and function

    Cell

    (2001)
  • K. Kobayashi et al.

    p140Sra-1 (Specifically Rac1-associated protein) is a novel specific target for Rac1 small GTPase

    J Biol Chem

    (1998)
  • S. Ceman et al.

    Identification of mouse YB1/p50 as a component of the FMRP-associated mRNP particles

    Biochem Biophys Res Commun

    (2000)
  • W. Paradee et al.

    Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function

    Neuroscience

    (1999)
  • D. Van Dam et al.

    Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice

    Behav Brain Res

    (2000)
  • C. Dobkin et al.

    Fmr1 knockout mouse has a distinctive strain-specific learning impairment

    Neuroscience

    (2000)
  • L. Chen et al.

    Fragile X mice develop sensory hyperreactivity to auditory stimuli

    Neuroscience

    (2001)
  • D.M. Nielsen et al.

    Alterations in the auditory startle response in Fmr1 targeted mouse model of fragile X syndrome

    Brain Res

    (2002)
  • S.A. Irwin et al.

    Evidence for altered fragile-X mental retardation protein expression in response to behavioral stimulation

    Neurobiol Learn Mem

    (2000)
  • P.K. Todd et al.

    Sensory stimulation increases cortical expression of the fragile X mental retardation protein in vivo

    Brain Res Mol Brain Res

    (2000)
  • J. Li et al.

    Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency

    Mol Cell Neurosci

    (2002)
  • G.S. Salomons et al.

    X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome

    Am J Hum Genet

    (2001)
  • R.E. Stevenson et al.
  • J. Chelly et al.

    Monogenic causes of X-linked mental retardation

    Nat Rev Genet

    (2001)
  • G. Imbert et al.

    FMR1 and mutations in fragile X syndrome: molecular biology, biochemistry, and genetics

  • P. Jin et al.

    Understanding the molecular basis of fragile X syndrome

    Hum Mol Genet

    (2000)
  • B. Bardoni et al.

    FMR1 gene and fragile X syndrome

    Am J Med Genet

    (2000)
  • D.S.D. fkjh
  • B. Coffee et al.

    Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. [Published erratum appears in Nat Genet 1999, 22:209]

    Nat Genet

    (1999)
  • P. Chiurazzi et al.

    Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene

    Hum Mol Genet

    (1999)
  • D. Devys et al.

    The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation

    Nat Genet

    (1993)
  • F. Corbin et al.

    The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes

    Hum Mol Genet

    (1997)
  • I.J. Weiler et al.

    Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

    Proc Natl Acad Sci USA

    (1997)
  • Y. Feng et al.

    Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes

    J Neurosci

    (1997)
  • D.E. Eberhart et al.

    The Fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals

    Hum Mol Genet

    (1996)
  • R.A. Fridell et al.

    A nuclear role for the Fragile X mental retardation protein

    EMBO J

    (1996)
  • F. Tamanini et al.

    Different targets for the fragile X related proteins revealed by distinct nuclear localization

    Hum Mol Genet

    (1999)
  • L. Wan et al.

    Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein

    Mol Cell Biol

    (2000)
  • F. Tamanini et al.

    Oligomerization properties of fragile-X mental-retardation protein (FMRP) and the fragile-X-related proteins FXR1P and FXR2P

    Biochem J

    (1999)
  • Dutch-Belgian Fragile X Consortium: FMR1 knockout mice: a model to study fragile X mental retardation. Cell 1994,...
  • Y. Feng et al.

    Translational suppression by trinucleotide repeat expansion at FMR1

    Science

    (1995)
  • H.J. Smeets et al.

    Normal phenotype in two brothers with a full FMR1 mutation

    Hum Mol Genet

    (1995)
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