Tissue and developmental regulation of fragile X mental retardation 1 exon 12 and 15 isoforms

Xie, Wen; Dolzhanskaya, Natalia; LaFauci, Giuseppe; Dobkin, Carl; Denman, Robert B.

doi:10.1016/j.nbd.2009.03.015

Cited by 29 publications

(36 citation statements)

References 42 publications

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“…The role of each isoform still needs to be clarified (Bassell and Warren 2008). Whereas FMRP isoforms are similarly expressed in many tissues and organs, the relative abundance of each isoform seems to be tissue specific (Kaufmann et al 2002;Xie et al 2009). FMRP is a multidomain RNA-binding protein able to recognize several coding and noncoding RNAs, including the brain cytoplasmic RNA BC1/BC200 (Ashley et al 1993;Johnson et al 2006;Napoli et al 2008;O'Donnell and Warren 2002;Siomi et al 1993;) and microRNAs (Edbauer et al 2010).…”

Section: An Insight Into the Structure Of The Fragile X Mental Retardmentioning

confidence: 99%

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Rubeis

Fernández

Buzzi

et al. 2012

Synaptic Plasticity

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The Fragile X syndrome (FXS) is the most frequent form of inherited mental retardation and also considered a monogenic cause of Autism Spectrum Disorder. FXS symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior. The disease is due to mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads, the two organs mainly affected in FXS patients. FMRP has multiple functions in RNA metabolism, including mRNA decay, dendritic targeting of mRNAs, and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired. Consistently, model organisms for the study of the syndrome recapitulate the phenotype observed in FXS patients, such as dendritic spine anomalies and defects in learning. Here, we review the fundamentals of genetic and clinical aspects of FXS, devoting a specific attention to ASD comorbidity and FXS-related diseases. We also review the current knowledge on FMRP functions through structural, molecular, and cellular findings. Finally, we discuss the neuroanatomical, electrophysiological, and behavioral defects caused by FMRP loss, as well as the current treatments able to partially revert some of the FXS abnormalities.

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Section: An Insight Into the Structure Of The Fragile X Mental Retardmentioning

confidence: 99%

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Rubeis

Fernández

Buzzi

et al. 2012

Synaptic Plasticity

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“…[5][6][7][8][9][10][11] The distribution and abundance of these isoforms may regulate the expression and functional properties of FMRP. Indeed, the FMR1 gene, which spans approximately 38 kb of genomic DNA and contains 17 exons, undergoes alternative splicing mainly involving inclusion or exclusion of exons 12 and 14 and the use of alternative splice acceptors in exons 15 and 17 5 9 (figure 1).…”

Section: Introductionmentioning

confidence: 99%

Differential increases of specificFMR1mRNA isoforms in premutation carriers

et al. 2014

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Background-Over 40% of males and ~16% of female carriers of a premutation FMR1 allele (55-200 CGG repeats) will develop Fragile X associated Tremor/Ataxia Syndrome (FXTAS), an adult onset neurodegenerative disorder while, about 20% of female carriers will develop Fragile X-associated Primary Ovarian Insufficiency. Marked elevation in FMR1 mRNA transcript levels has been observed with premutation alleles, and RNA toxicity due to increased mRNA levels is the leading molecular mechanism proposed for these disorders. However, although the FMR1 gene undergoes alternative splicing, it is unknown if all or only some of the isoforms are overexpressed in premutation carriers and which isoforms may contribute to the premutation pathology.

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“…The FMR1 mRNA has multiple isoforms in brain, including isoform 3 (Ashley et al, 1993;Xie et al, 2009), but their protein products have not been visualized in the absence of the autosomal paralogs, FXR1P and FXR2P. To examine the brain isoforms of FMRP, we used a serial immunoprecipitation strategy described previously (Ceman et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the state of a cell might dictate which FMRP isoforms are present, leading to the execution of a specific function. When P19 cells were induced to differentiate, splice site usage was shifted to 15c, suggesting that isoform 3 is required for neurite production or function (Xie et al, 2009). In conclusion, understanding how the RGG box is regulated will give insight into how FMRP binds its target mRNAs, assembles with granules and regulates translation.…”

Section: Resultsmentioning

confidence: 99%

A new regulatory function of the region proximal to the RGG box in the Fragile X mental retardation protein

Blackwell

Ceman

2011

Journal of Cell Science

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SummaryFragile X mental retardation protein (FMRP) is required for normal cognition. FMRP has two autosomal paralogs, which although similar to FMRP, cannot compensate for the loss of FMRP expression in brain. The arginine-and glycine-rich region of FMRP (the RGG box) is unique; it is the high-affinity RNA-binding motif in FMRP and is encoded by exon 15. Alternative splicing occurs in the 59 end of exon 15, which is predicted to affect the structure of the distally encoded RGG box. Here, we provide evidence that isoform 3, which removes 25 amino acids from the 59 end of exon 15, has an altered conformation that reduces binding of a specific antibody and renders the RGG box unable to efficiently associate with polyribosomes. Isoform 3 is also compromised in its ability to form granules and to associate with a key messenger ribonucleoprotein Yb1 (also known as p50, NSEP1 and YBX1). Significantly, these functions are similarly compromised when the RGG box is absent from FMRP, suggesting an important regulatory role of the N-terminal region encoded by exon 15.

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Tissue and developmental regulation of fragile X mental retardation 1 exon 12 and 15 isoforms

Cited by 29 publications

References 42 publications

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Molecular and Cellular Aspects of Mental Retardation in the Fragile X Syndrome: From Gene Mutation/s to Spine Dysmorphogenesis

Differential increases of specificFMR1mRNA isoforms in premutation carriers

A new regulatory function of the region proximal to the RGG box in the Fragile X mental retardation protein

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