Ladd, P. al. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum. Mol. Genet.16, 3174-3187

Department of Pediatrics, University of California, Davis, Davis, California, United States
Human Molecular Genetics (Impact Factor: 6.39). 01/2008; 16(24):3174-87. DOI: 10.1093/hmg/ddm293
Source: PubMed


Expansion of the polymorphic CGG repeats within the 5′-UTR of the FMR1 gene is associated with variable transcriptional regulation of FMR1. Here we report a novel gene, ASFMR1, overlapping the CGG repeat region of FMR1 and transcribed in the antisense orientation. The ASFMR1 transcript is spliced, polyadenylated and exported to the cytoplasm. Similar to FMR1, ASFMR1 is upregulated in individuals with premutation alleles and is not expressed from full mutation alleles. Moreover, it exhibits
premutation-specific alternative splicing. Taken together, these observations suggest that in addition to FMR1, ASFMR1 may contribute to the variable phenotypes associated with the CGG repeat expansion.

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    • "Thus FXS derives from the loss of FMR1 mRNA and protein FMRP. We and others have identified four non-coding transcripts with abnormal expression in response to Fragile X repeat expansions at the FMR1 locus (Ladd et al., 2007; Khalil et al., 2008; Pastori et al., 2014), but their role in FXS/FXTAS/FXPOI phenotypes remains to be determined. The vast majority of the human transcriptome is comprised of either long [>200 nucleotides (nt)] or short ncRNAs (Cheng et al., 2005; Banfai et al., 2012; Djebali et al., 2012). "
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    ABSTRACT: CGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism Fragile X Syndrome (FXS), or adult-onset neurodegeneration Fragile X-associated Tremor/Ataxia Syndrome. However, the FMR1 locus is complex and encodes several long non-coding RNAs, whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. "Full"-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. Since the two transcripts do not exhibit cis-regulation of one another, we examined the potential for FMR4 to regulate target genes at distal genomic loci using gene expression microarrays. We identified FMR4-responsive genes, including the methyl-CpG-binding domain protein 4 (MBD4). Furthermore, we found that in differentiating human neural precursor cells, FMR4 expression is developmentally regulated in opposition to expression of both FMR1 (which is expected to share a bidirectional promoter with FMR4) and MBD4. We therefore propose that FMR4's function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.
    Full-text · Article · Aug 2015 · Frontiers in Genetics
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    • "This cannot be attributed to failed CTCF binding at the FMR1 locus, as previously proposed, since no enrichment for CTCF was found in FMR1 in both WT and affected HESCs. These results are different from the reports by Ladd et al. (2007) and Lanni et al., (2013) and may stem from the different cell types employed. "
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    ABSTRACT: Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5′-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.
    Full-text · Article · Nov 2014 · Stem Cell Reports
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    • "The antisense rCGGs may also sequester proteins, as proposed for the sense transcript. Furthermore, since the repeat is located in a putative open reading frame on some of the antisense transcripts, it could produce a repeat-containing protein, in this case a polyproline-containing protein, which could contribute to disease pathology [76]. "
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    ABSTRACT: Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI.
    Full-text · Article · Aug 2014 · Journal of Neurodevelopmental Disorders
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