Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome

Bell, M. V.; Hirst, Mark C.; Nakahori, Yutaka; MacKinnon, Ruth N.; Roche, A.; Flint, T; Jacobs, Patricia A.; Tommerup, Niels; Tranebjærg, Lisbeth; Froster-Iskenius, U.; Kerr, Bredford; Turner, Gillian; Lindenbaum, R H; Winter, R M; Prembrey, M.; Thibodeau, Stephen N.; Davies, Kay E.

doi:10.1016/0092-8674(91)90514-y

Cited by 316 publications

(209 citation statements)

References 24 publications

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“…Methylation of such CpG sites has been shown to inhibit gene transcription (6)(7)(8)(9). Such a change has been correlated with a region of chromosome instability and with decreased expression of the gene responsible for the inherited mental retardation disease, fragile X syndrome (28)(29)(30). Also, CpG dinucleotides are mutational hotspots, since 5-methylcytidine residues are highly mutable and engage inC --T transitions through deamination (10)(11)(12).…”

Section: Methodsmentioning

confidence: 99%

Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells.

Issa

Herman

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

231

144

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Abnormal regional increases in DNA methylatlon, which have potential for causing gene inactivation and chromosomal instability, are consistently found in immortalized and tumorigenic ceUls. Increased DNA methyltranderase activity, which is also a characteristic of such cells, is a candidate to mediate these abnormal DNA methylation patterns. We now show that, in NIH 3T3 mouse fibroblasts, constitutive overexpression of an exogenous mouse DNA methyltransferase gene results in a marked increase in overall DNA methylation which is accompanied by tumorigenic transformation. These transformation changes can also be elicited by dexamethasone-inducible expression of an exogenous DNA methyltransferase gene. Our findings provide strong evidence that the increase in DNA methyltransferase activity associated with tumor progression could be a key step in carcinogenesis and provide a model system that can be used to further study this possibility.Abnormal patterns of DNA methylation are a consistent molecular feature of immortalized and neoplastic cells (for review, see refs. 1 and 2). An important aspect of these changes is the abnormal de novo methylation (2-4) of normally unmethylated clusters of cytosine-guanosine dinucleotides, or "CpG islands," which are usually located in the 5' region of genes (5). This abnormal methylation has been associated with changes of chromatin structure (3, 4) that can inhibit gene expression (6-9). DNA methylation could also result in changes in DNA sequences, since methylated cytosine is a highly mutable base in the eukaryotic genome (10-12).One potential mechanism for establishing abnormal patterns of DNA methylation in neoplastic cells involves the increases in DNA methyltransferase (DNA MTase) activity that we (13) and others (14)

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Section: Methodsmentioning

confidence: 99%

Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells.

Issa

Herman

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

231

144

View full text Add to dashboard Cite

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“…Based on the size of the expansion, individuals are classified as having normal (5-54 trinucleotide repeats), premutated (55-200 repeats), or fully mutated (O200 repeats) alleles (Fu et al 1991, Oberle et al 1991, Rousseau et al 1995. Full mutated alleles usually result in hypermethylation of the CpG site in the promoter region of the FMR1 gene (Bell et al 1991), which leads to gene silencing; the subsequent absence of the protein is therefore responsible for FXS. Conversely, carriers of the premutation have increased levels of FMR1 mRNA (twofold to eightfold in lymphocytes) due to increased transcription rate of the gene (Tassone et al 2000(Tassone et al , 2007.…”

Section: Introductionmentioning

confidence: 99%

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

et al. 2013

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Fragile X mental retardation protein (FMRP) belongs to a small family of RNA-binding proteins. Its absence or inactivity is responsible for fragile X syndrome, the most common cause of inherited mental retardation. Despite its ubiquitous expression, FMRP function and expression remain almost understudied in non-neuronal tissues, though previous studies on germline development during oogenesis may suggest a special function of this protein also in ovarian tissue. In addition, the well-documented association of FMR1 premutation state with fragile X-related premature ovarian insufficiency adds interest to the role of FMRP in ovarian physiology. The aim of the present work was to investigate the expression of Fmr1 mRNA and its protein, FMRP, at different stages of rat follicular development. By immunohistochemical studies we demonstrated FMRP expression in granulosa, theca and germ cells in all stages of follicular development. In addition, changes in Fmr1 expression, both at the protein and mRNA levels, were observed. FMRP levels increased upon follicular development while preantral and early antral follicles presented similar levels of Fmr1 transcripts with decreased expression in preovulatory follicles. These observations suggest that Fmr1 expression in the ovary is regulated at different and perhaps independent levels. In addition, our results show expression of at least four different isoforms of FMRP during all stages of follicular growth with expression patterns that differ from those observed in brain and testis. Our study shows a regulated expression of Fmr1, both at mRNA and protein levels, during rat follicular development.

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“…Abnormal methylation of CpG dinucleotides in the upstream promoter region is a repeat-expansion-associated phenomenon in fragile X patients which results in repression of transcription of FMR1 gene and consequently the absence of the RNA binding protein FMRP. [1][2][3][4] There is also a strong correlation between the severity of disease symptoms and the level of DNA methylation in and around CGG repeats and the promoter of FMR1 gene. 1,5 Premutation alleles, with a high propensity for expansion to full mutation, have repeat range of 55 to 200 and are generally unmethylated.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of DNA methylation in transgenic mice with unstable CGG repeats from FMR1 gene

et al. 2010

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Physical mapping across the fragile X: Hypermethylation and clinical expression of the fragile X syndrome

Cited by 316 publications

References 24 publications

Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells.

Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells.

Expression of fragile X mental retardation protein and Fmr1 mRNA during folliculogenesis in the rat

Comparative analysis of DNA methylation in transgenic mice with unstable CGG repeats from FMR1 gene

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