Human Chromosomal Fragile Site FRA16B Is an Amplified AT-Rich Minisatellite Repeat

Yu, Shaohua; Mangelsdorf, Marie; Hewett, Duncan R.; Hobson, Lynne; Baker, Elizabeth; Eyre, Helen J.; Lapsys, Naras M.; Paslier, Denis Le; Doggett, Norman A.; Sutherland, Grant R.; Richards, Robert I.

doi:10.1016/s0092-8674(00)81875-9

Cited by 170 publications

(126 citation statements)

References 34 publications

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“…The fragile sites can be classi®ed as common or rare, based upon the frequency of their occurrence in the human population (Sutherland and Hecht, 1985). Expression of the known cloned rare fragile sites is associated with the expansion of trinucleotide or minisatellite sequences (Fu et al, 1991;Knight et al, 1993;Parrish et al, 1994;Jones et al, 1994;Yu et al, 1997). Common fragile sites appear to be present in all individuals and most are induced by the DNA polymerase a inhibitor aphidicolin (Glover et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Frequent homozygous deletions in the FRA3B region in tumor cell lines still leave the FHIT exons intact

et al. 1998

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FRA3B at human chromosomal band 3p14.2 is the most active common fragile site in the human genome. The molecular mechanism of fragility at this region remains unknown but does not involve expansion of a trinucleotide or minisatellite repeat as has been observed for several of the cloned rare fragile sites. Deletions and rearrangements at FRA3B have been observed in a number of distinct tumors. The recently identi®ed putative tumor suppressor gene FHIT spans FRA3B, and various groups have reported identifying deletions in this gene in dierent tumors. Using a high density of PCR ampli®able markers within FRA3B searching for deletions in the FRA3B region, we have analysed 21 tumor cell lines derived from renal cell, pancreatic, and ovarian carcinomas. We found a commonly deleted region in the renal cell and ovarian carcinoma cell lines located in the middle of an HPV16 viral integration site. Despite the presence of deletions in the FRA3B region in most of the cell lines, we did not detect alterations in FHIT exons in any of the cell lines examined. Thus, deletions of 3p14.2 in these carcinoma cell lines may simply re¯ect instability of the FRA3B region during tumor progression.

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Section: Introductionmentioning

confidence: 99%

Frequent homozygous deletions in the FRA3B region in tumor cell lines still leave the FHIT exons intact

et al. 1998

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“…The instability of fragile sites at the molecular and cytogenetic levels can lead to disease manifestation by silencing adjacent gene(s) (2,3) or by causing chromosomal rearrangements and disrupting gene expression (4). Several rare fragile sites have been characterized at the molecular level by positional cloning using families expressing these sites (4)(5)(6)(7)(8)(9). The expression of these sites is associated with expanded CGG trinucleotide repeats or with an expanded 33-bp AϩT-rich minisatellite repeats.…”

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confidence: 99%

Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

Rahat

Scherer

et al. 1998

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

202

240

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Common fragile sites are chromosomal loci prone to breakage and rearrangement, hypothesized to provide targets for foreign DNA integration. We cloned a simian virus 40 integration site and showed by f luorescent in situ hybridization analysis that the integration event had occurred within a common aphidicolin-induced fragile site on human chromosome 7, FRA7H. A region of 161 kb spanning FRA7H was defined and sequenced. Several regions with a potential unusual DNA structure, including high-f lexibility, lowstability, and non-B-DNA-forming sequences were identified in this region. We performed a similar analysis on the published FRA3B sequence and the putative partial FRA7G, which also revealed an impressive cluster of regions with high f lexibility and low stability. Thus, these unusual DNA characteristics are possibly intrinsic properties of common fragile sites that may affect their replication and condensation as well as organization, and may lead to fragility.

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“…For example, an expanded 33-bp, AT-rich minisatellite results in the common distamycin A-sensitive fragile site, FRA16B causing fragile X syndrome. 26 The small alleles containing 7-12 sequenceheterogeneous repeats are enlarged up to 2000 copies of one repeat type in FRA16B. Thirdly, recent examples show that minisatellite expansion disrupt gene expression by yet unknown mechanism.…”

Section: Discussionmentioning

confidence: 98%

“…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%

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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Human Chromosomal Fragile Site FRA16B Is an Amplified AT-Rich Minisatellite Repeat

Cited by 170 publications

References 34 publications

Frequent homozygous deletions in the FRA3B region in tumor cell lines still leave the FHIT exons intact

Frequent homozygous deletions in the FRA3B region in tumor cell lines still leave the FHIT exons intact

Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

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

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