Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation

Knight, Samantha J. L.; Flannery, Angela V.; Hirst, Mark C.; Campbell, Louise J.; Christodoulou, Zóe; Phelps, Stephanie F.; Pointon, Jennifer J.; Middleton‐Price, Helen; Barnicoat, Angela; Pembrey, Marcus; Holland, Jill; Oostra, Ben A.; Bobrow, Martin; Davies, Kay E.

doi:10.1016/0092-8674(93)90300-f

Cited by 484 publications

(264 citation statements)

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“…1 To date more than 30 MRX loci have been described based on linkage with lod scores of > 2.0 in different families. 2,3,4 The second category includes the fragile X (fraXA) 5 and the fraXE 6 syndromes. The third group comprises syndromic XLMR, ie MR syndromes with additional clinical features such as neurological and metabolic symptoms, auditory problems, and dysmorphological stigmata.…”

Section: Introductionmentioning

confidence: 99%

MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1–p22.13

1998

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A previously unrecognised X-chromosomal mental retardation syndrome is described. Clinical hallmarks are mental retardation, epileptic seizures, hypogonadism, and -genitalism, microcephaly and obesity. Life expectancy of patients is less than two years. Based on the major clinical symptoms this condition is referred to by the acronym MEHMO. Haplotype and two-point linkage analyses in a large three-generation family assign the disease locus to Xp21.1-p22.13, to a region that is flanked by CYBB and DXS365.

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Section: Introductionmentioning

confidence: 99%

MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1–p22.13

1998

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“…Microsatellites consisting of variable numbers of a dinucleotide or trinucleotide repeat often provide genetic markers for gene mapping [42]. Recently, genetic linkage analyses using microsatellites have revealed several genes or loci responsible for inherited diseases including hypertension [39], FRAXE mental retardation [40], and Huntington's disease [41]. In intron 13, we also detected 35 repeats of a dinucleotide (CA), that are different from the 37 repeats reported by Marsden et al [18].…”

Section: Existence Of Minisatellite Sequences and Tandem Repeats In Imentioning

confidence: 50%

Cloning and structural characterization of the human endothelial nitric‐oxide‐synthase gene

Miyahara

Kawamoto

Sase

et al. 1994

European Journal of Biochemistry

150

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Nitric oxide accounts for the activity of endothelium-derived relaxing factor, which seems to have an important role in vasodilation and inhibition of platelet aggregation. In endothelial cells, one isoform of nitric-oxide synthase is constitutively expressed. Analysis of the cDNA encoding the human endothelial nitric-oxide synthase revealed that the mRNA is 4.1 kb in size and that the translated protein consists of 1203 amino acids. We have cloned a genomic DNA encoding the human endothelial nitric-oxide synthase and analyzed the entire nucleotide sequence of the gene. The gene consists of 26 exons with a total size of 21 kb. The 5' flanking region of the gene lacks TATA boxes, but it contains putative Spl-binding sites in (G+C)-rich regions. Of particular interest is the fact that a shear-stress-responsive element is located at position -985, which probably regulates the nitric-oxide-synthase gene in response to fluid mechanical forces at the transcriptional level in the vascular endothelium. Two minisatellite sequences are detectable in introns 2 and 8; a 32-bp consensus sequence repeats 38 times and a 57-bp consensus sequence repeats ten times. We found polymorphisms of the BarnHI fragment containing the former minisatellite sequence in genomic DNA from pedigree family members. Furthermore, five tandem repeats of a 27-bp core consensus sequence and 35 repeats of a dinucleotide (CA) are located in introns 4 and 13, respectively. These repeat sequences will probably provide genetic markers for gene mapping and linkage analysis of inherited diseases including cardiovascular diseases.Nitric oxide has been recently implicated in a number of diverse physiological processes, including smooth muscle relaxation, inhibition of platelet aggregation, neurotransmission, immune regulation and penile erection 11, 21. Nitric oxide is produced from L-arginine by nitric-oxide synthase with a concomitant production of L-citrulline. There appears to be at least three distinct isoforms of nitric-oxide synthase [l-41. All three isoforms contain consensus sequences for the binding of FMN, FAD, and NADPH cofactors, and the structures of the isoforms have close homology to cytochrome P-450 reductase 11, 2, 51.Endothelium-derived relaxing factor 161 is important in the regulation of vasomotor tone and blood flow by inhibiting smooth muscle contraction and platelet aggregation [7]. Recently, several groups reported that nitric oxide accountsCorrespondence to

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“…In fact, the expanded and hypermethylated CGG sequence is replicating so late that (under particular culture conditions) it is not duplicated at mitosis and cannot condense at metaphase. All these fragile sites (including FRAXA, FRAXE, FRAXF, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A) are located in promoters and their expression associates with silencing of the respective genes [Oberlé et al, 1991;Knight et al, 1993;Ritchie et al, 1994;Nancarrow et al, 1995;Jones et al, 2000;Sarafidou et al, 2004;Debacker et al, 2007;Winnepenninckx et al, 2007]. …”

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confidence: 99%

Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation

Cited by 484 publications

References 44 publications

MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1–p22.13

MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1–p22.13

Cloning and structural characterization of the human endothelial nitric‐oxide‐synthase gene

Epigenetics, fragile X syndrome and transcriptional therapy

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