Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy

Lalioti, Maria D.; Scott, Hamish S.; Burési, Catherine; Rossier, Colette; Bottani, Armand; Morris, Michael A.; Malafosse, Alain; Antonarakis, Stylianos E.

doi:10.1038/386847a0

Cited by 339 publications

(253 citation statements)

References 29 publications

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“…A candidate-gene approach to positional cloning identified alteration of the cystatin B (CSTB) gene as the cause of EPM1. In addition to missense point mutations in the coding region, Lalioti et al (1997) and Lafreniere et al (1997) found expansion of a 12-nucleotide repeat located about 70 bp upstream of the transcription start site in the majority of EPM1 alleles, and also revealed that expansion of this VNTR reduced levels of CSTB mRNA in blood. Meloni et al (1998) provided further evidence that minisatellites can play significant roles in the regulation of transcription when they reported that a polymorphic tetranucleotide repeat in an intron of the tyrosine hydroxylase gene functions as an enhancer element.…”

Section: Vntrs As Transcriptional Regulatorsmentioning

confidence: 99%

VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators

1998

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VNTR (variable number of tandem repeat) markers, also called single-copy minisatellites, were originally isolated from human DNA as highly informative restriction fragment length polymorphisms for mapping purposes. Evidence has lately emerged that some VNTR sequences play significant roles in the regulation of transcription, and that some may also influence the translational efficiency or stability of mRNA, or modify the activity of proteins by altering their structure. Some apparent associations of VNTR sequences with personality traits or with susceptibility to diseases have strengthened the likelihood that these tandemly-repeated genomic elements are of physiological and biological importance. In this review, we summarize recent progress in efforts to clarify mechanisms involving VNTR sequences.

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Section: Vntrs As Transcriptional Regulatorsmentioning

confidence: 99%

VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators

1998

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“…The results revealed that the relative orientations of two GAA⅐TTC repeat tracts had no influence on the recombination frequency. 2 Thus, the inhibition of recombination between oppositely oriented tracts appears to be a (CTG⅐CAG) triplet repeat-dependent phenomenon (see "Discussion"). Nevertheless, when the tracts were in opposite orientations, the apparent recombination frequency was the highest when the (CTG⅐CAG) 98 repeats in the replicating plasmid (the pBR322 derivative) were in orientation II (Table III).…”

Section: Table II Plasmids Used In This Studymentioning

confidence: 99%

Long CTG·CAG Repeats from Myotonic Dystrophy Are Preferred Sites for Intermolecular Recombination

Pluciennik

Iyer

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et al. 2002

Journal of Biological Chemistry

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Homologous recombination was shown to enable the expansion of CTG⅐CAG repeat sequences. Other prior investigations revealed the involvement of replication and DNA repair in these genetic instabilities. Here we used a genetic assay to measure the frequency of homologous intermolecular recombination between two CTG⅐CAG tracts. When compared with non-repeating sequences of similar lengths, long (CTG⅐CAG) n repeats apparently recombine with an ϳ60-fold higher frequency. Sequence polymorphisms that interrupt the homogeneity of the CTG⅐CAG repeat tracts reduce the apparent recombination frequency as compared with the pure uninterrupted repeats. The orientation of the repeats relative to the origin of replication strongly influenced the apparent frequency of recombination. This suggests the involvement of DNA replication in the recombination process of triplet repeats. We propose that DNA polymerases stall within the CTG⅐CAG repeat tracts causing nicks or double-strand breaks that stimulate homologous recombination. The recombination process is RecA-dependent.Micro-and minisatellite instability has been associated with human genetic diseases (1-4). Approximately 14 hereditary neurological diseases are caused by the genetic instabilities of triplet repeat sequences (TRS) 1 in or near relevant genes (reviewed in Ref. 1). Long tracts of repeating CTG⅐CAG sequences are responsible for myotonic dystrophy and several other diseases. Normal individuals have 5-37 repeats in the myotonic dystrophy protein kinase gene, whereas the mutations (expansions) can be in the range of 50 -3000 repeats. Thus, an explosive allele length change during intergenerational transmission can occur in this autosomal dominant disease, thus causing an increase in the severity of the disease and a decrease of the age at onset (anticipation).The mechanisms of genetic instabilities have been widely investigated in the past 6 years (1). DNA replication (5-8) and repair including methyl-directed mismatch repair (9 -11), nucleotide excision repair (12), DNA polymerase III exonucleolytic proofreading (13), and double-strand break repair (14) have been implicated.Repetitive sequences promote homologous recombination in prokaryotic as well as eukaryotic systems, presumably by virtue of forming unusual DNA secondary structures (15)(16)(17)(18)(19)(20)(21)(22). In fact, homologous recombination has been implicated in the instability of repetitive sequences (23-26). Similar findings have also been made with CTG⅐CAG repeats using a two-plasmid system in Escherichia coli (27,28). Multiple fold expansions, deletions, and the exchange of point mutations between tracts were found in this system; these events were dependent on the presence of TRS tracts on both plasmids, CTG⅐CAG repeat lengths longer than 30, and a functional recA gene.Previously (29), it was proposed that CTG⅐CAG tracts might function as recombination hot spots in the bovine genome. More recently, Young et al. (30) surveyed the genome of Saccharomyces cerevisiae and suggested that these repeats cou...

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“…32 These examples are associated with an increased risk of insulin-dependent diabetes and several cancers, respectively. The palindromic sequence GGGCTAGCCC present in each repeat of the TFF2 intron suggests the existence of a functional DNA Figure 4 Evolutionary origin of the 25 TFF2 is most prominent in porcine pancreas, and is present in mouse and rat acinar cells of the pancreas, whereas it is not found in the human pancreas. 2,33 Although no direct relationship of TFF2 with a human disease is yet proven,TFF2 and TFF1 transcription is coordinately upregulated in some adenomas of stomach, pancreas, and biliary tract.…”

Section: Discussionmentioning

confidence: 99%

“…The expansion of a GC-rich 12-bp repeat unit is responsible for a monogenic form of epilepsy termed EPM1. 25,34 This repeat, normally present in 2-3 copies in normal alleles of the promoter region of the gene encoding cystatin B is expanded to a large insertion (600-900 bp) leading to inhibition of transcription in affected patients.…”

Section: Discussionmentioning

confidence: 99%

“…However, it may turn out to be of functional relevance in modulating gene expression due to a binding site for a transcription factor, or interfering with gene expression, or causing genetic instability. Recent examples related to these functions are the diabetes susceptibility locus IDDM2, 23 a minisatellite expansion in a noncoding part of a gene also found in 21q22.3 that is responsible for a monogenic form of epilepsy, 24,25 or the fragile X syndrome caused by minisatellite expansion in FRA16B. 26 …”

Section: Introductionmentioning

confidence: 99%

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A novel 25 bp tandem repeat within the human trefoil peptide gene TFF2 in 21q22.3: polymorphism and mammalian evolution

et al. 1998

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Trefoil peptides belong to a family of small secretory proteins characterised by three intrachain disulfide bonds forming the trefoil motif (TFF-domain). They serve to maintain or repair the epithelial mucosa, and promote cell migration. They are predominantly found in gastrointestinal tissues, and are upregulated around areas of epithelial damage, and in meta-and neoplasia. The corresponding three genes are clustered in human 21q22.3. TFF2 is the only human one encoding two TFF-domains on separate exons. In between (intron 2), a novel 25 bp sequence is located that is tandemly repeated approximately 48 times, but is unique in the human genome. A diallelic polymorphism with a second allele comprising approximately 53 repeat units is present among individuals. Both alleles were cloned on BAC recombinants. In Caucasians (n = 78) the allele frequencies found are 0.85 and 0.15, respectively, representing a frequency of heterozygosity of 26%. Ape and monkey species exhibit homologous repeats of shorter total array length, whereas none is found in other mammals.

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Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy

Cited by 339 publications

References 29 publications

VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators

VNTR (variable number of tandem repeat) sequences as transcriptional, translational, or functional regulators

Long CTG·CAG Repeats from Myotonic Dystrophy Are Preferred Sites for Intermolecular Recombination

A novel 25 bp tandem repeat within the human trefoil peptide gene TFF2 in 21q22.3: polymorphism and mammalian evolution

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