FMRP Associates with Polyribosomes as an mRNP, and the I304N Mutation of Severe Fragile X Syndrome Abolishes This Association

Feng, Yue; Absher, Devin; Eberhart, Derek E.; Brown, Victoria; Malter, Henry; Warren, Stephen T.

doi:10.1016/s1097-2765(00)80012-x

Cited by 471 publications

(460 citation statements)

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“…FMRP is associated with actively translating polyribosomes in an RNA-dependent manner via messenger ribonucleoprotein (mRNP) particles [7]. A missense mutation in the second KH domain of FMRP (I304N), which results in severe mental retardation, prevents this polyribosome association, suggesting that the association of FMRP with polyribosomes is functionally important [7].…”

Section: Glossarymentioning

confidence: 99%

“…60% amino acid identity and contain two types of RNA-binding motifs: two ribonucleoprotein K homology domains (KH domains) and a cluster of arginine and glycine residues (RGG box). Owing to their similarities, it has been postulated that FXR1P and FXR2P can partially compensate for the loss of FMRP, although expression levels of both FXR1P and FXR2P are not altered in the cells from fragile X patients or the Fmr1-knockout mice [7]. The fragile X-related gene family has been well conserved during evolution.…”

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confidence: 99%

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New insights into fragile X syndrome: from molecules to neurobehaviors

Jin

Warren

2003

Trends in Biochemical Sciences

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190

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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...

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Section: Glossarymentioning

confidence: 99%

mentioning

confidence: 99%

New insights into fragile X syndrome: from molecules to neurobehaviors

Jin

Warren

2003

Trends in Biochemical Sciences

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190

124

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“…A hypothesis explaining the probable function of FMR1 is that it might be involved in binding RNA transcripts within the nucleus and transporting them across the nuclear membrane for translation in the cytoplasm. In the Case of the point mutation in addition to its inability to bind effectively to the transcripts generated, the mutant FMRP forms abnormally small mRNP particles which fail to be transported across the nucleus and therefore are not selected for translation (30). The fact that FMR1 is expressed in actively dividing cells, cosediments with 60s ribosomes and strongly interacts with Rab40, a protein found in the nuclear pores seem to support its postulated function (31).…”

Section: Fragile X Mental Retardation Protein (Fmrp)mentioning

confidence: 99%

Chromosomal fragility and human genetic disorders

Baskaran

Brahmachari

2000

Indian J Clin Biochem

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The first report of X-linked mental retardation correlated with the presence of marker chromosome came in 1940. It was in 1990 that the molecular basis of fragile X syndrome was deciphered. This elucidation marked the discovery of a novel process of mutation designated as dynamic mutations, resulting in the expansion of a triplet repeat sequence within the human genome. Subsequently several human genetic disorders involving triplet repeat expansion have beer= discovered. Almost all the disorders are known to affect the nervous system and/or the brain. This review presents an overview of fragile sites in the genome and the molecular genetics of fragile X syndrome.

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“…These mRNP are associated with the translating ribosomes (polyribosomes) as demonstrated by the use of translation initiation inhibitors (Corbin et al, 1997;Feng et al, 1997). Still, the question of a functional interaction between FMRP and the ribosome seems unsolved.…”

Section: The Fmrp Mrnp Particle(s)mentioning

confidence: 99%

“…After an initial conclusion that FMRP was intimately associated with the ribosome, further studies suggested that FMRP does not interact directly with the ribosomes themselves but rather through the interaction with mRNA. Indeed, ribosomes can be depleted from mRNPs by EDTA treatment, while FMRP remains associated to a complex of large size, with a sedimentation peak centered at 100S, clearly distinct from heaviest 60S ribosomal subunits (Feng et al, 1997;Ohashi et al, 2002). However, the recent report of the isolation of ribosomal proteins directly associated with the Drosophila FMRP homolog suggests that a direct interaction between FMRP and the ribosome is likely to occur at some point .…”

Section: The Fmrp Mrnp Particle(s)mentioning

confidence: 99%

The RNA binding protein FMRP: new connections and missing links

Schaeffer

Beaulande

Ehresmann

et al. 2003

Biology of the Cell

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The loss of the fragile X mental retardation protein (FMRP) is responsible for the most common cause of inherited mental retardation called the fragile X syndrome. FMRP is suspected to participate in the synaptic plasticity of neurons by acting on posttranscriptional control of gene expression. FMRP is an RNA binding protein that associates with mRNAs together with other proteins to form large ribonucleoprotein complexes. These complexes are proposed to participate in the transport, localization and translation of target mRNAs. Progress has been made recently in the identification of the mRNAs and the proteins present in these complexes and a possible connection with the micro-RNA dependent regulatory pathway has been established.

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FMRP Associates with Polyribosomes as an mRNP, and the I304N Mutation of Severe Fragile X Syndrome Abolishes This Association

Cited by 471 publications

References 44 publications

New insights into fragile X syndrome: from molecules to neurobehaviors

New insights into fragile X syndrome: from molecules to neurobehaviors

Chromosomal fragility and human genetic disorders

The RNA binding protein FMRP: new connections and missing links

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