DNA-Triplet Repeats and Neurologic Disease

Rosenberg, Roger N.

doi:10.1056/nejm199610173351609

Cited by 36 publications

(13 citation statements)

References 25 publications

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“…pMP145 and pRW3832 contain (GAA) 10 -A(GAA)GAG(GAA) 4 in the lagging and leading strand templates, respectively. pRW3835 and pRW3821 contain (GAA) 24 A(GAA)GAG-(GAA) 4 and GAGGA(GAA) 48 A 3 (GAA)A 2 (GAA) 10 in the leading strand template, respectively. pRW3830 contains (GAA) 40 A(GAA)GAG(GAA) 4 in the lagging strand template.…”

Section: Discussionmentioning

confidence: 99%

“…FRDA patients carrying two expanded GAA⅐TTC repeats show very low levels of mature frataxin transcript (1,7,8) and of frataxin (9), indicating suppressed gene expression. Such a defect may be caused either by reduced transcription or by abnormal post-transcriptional processing (1,9,10). Together with the identification of frataxin point mutations resulting in a defective or truncated protein, this finding defines FRDA as a frataxin deficiency disease, in accordance with its recessive inheritance.…”

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confidence: 95%

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Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo

Ohshima¹,

Montermini²,

Wells³

et al. 1998

Journal of Biological Chemistry

296

267

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Friedreich ataxia (FRDA) is associated with the expansion of a GAA⅐TTC triplet repeat in the first intron of the frataxin gene, resulting in reduced levels of frataxin mRNA and protein. To investigate the mechanisms by which the intronic expansion produces its effect, GAA⅐TTC repeats of various lengths (9 to 270 triplets) were cloned in both orientations in the intron of a reporter gene. Plasmids containing these repeats were transiently transfected into COS-7 cells. A length-and orientation-dependent inhibition of reporter gene expression was observed. RNase protection and Northern blot analyses showed very low levels of mature mRNA when longer GAA repeats were transcribed, with no accumulation of primary transcript. Replication of plasmids carrying long GAA⅐TTC tracts (ϳ250 triplets) was greatly inhibited in COS-7 cells compared with plasmids carrying (GAA⅐TTC) 9 and (GAA⅐TTC) 90 . Replication inhibition was five times greater for the plasmid whose transcript contains (GAA) 230 than for the plasmid whose transcript contains (UUC) 270 . Our in vivo investigation revealed that expanded GAA⅐TTC repeats from intron I of the FRDA gene inhibit transcription rather than posttranscriptional RNA processing and also interfere with replication. The molecular basis for these effects may be the formation of non-B DNA structures.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo

Ohshima¹,

Montermini²,

Wells³

et al. 1998

Journal of Biological Chemistry

296

267

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“…Detailed sequence analyses of mutation patterns at individual loci have been performed especially for trinucleotides associated with diseases (Rosenberg 1996) and some tetranucleotides (Mahtani and Willard 1993;Talbot et al 1995). Minisatellites have also been analyzed (Jeffreys et al 1994).…”

Section: ‫3מ‬mentioning

confidence: 99%

“…Instability of trinucleotide repeats is involved with certain neurodegenerative conditions (for review, see Rosenberg 1996), suggesting that underlying mutational mechanisms may be responsible for genetic morbidity. Polymorphic dinucleotide repeats have been used extensively for gene mapping (Dib et al 1996), forensic identification (Edwards et al 1992) and studying the history of human population (Bowcock et al 1994;Deka et al 1995).…”

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confidence: 99%

The Complex Mutation Pattern of a Microsatellite

Macaubas¹,

Li²,

Hallmayer³

et al. 1997

Genome Res.

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DQCAR is a (CA)n microsatellite located in the HLA class II region and tightly linked toHLA–DQB1. Previous studies showed a strikingly low level of size variation in DQCAR alleles within an extensive subfamily of HLA–DQ subtypes (DQ1). DQCAR alleles in non-DQ1 subtypes showed a higher degree of size polymorphism. In this study sequence analysis demonstrates that DQ1- associated DQCAR alleles have a single C → A nucleotide substitution interupting the CA repeat array. Frequent CA → GA mutations are also observed in DQ1-associated microsatellites with identical allele sizes. In contrast, DQCAR alleles associated with non-DQ1 haplotypes display a perfect CA repeat sequence and the variation in allele size is attributable only to differences in the number of CA repeats. Our results imply that several mutational mechanisms are involved in the generation of allelic diversity within the same microsatellite locus. The possibility of different mutation rates in the same locus should to be taken into account when using these markers in evolutionary and disease studies.[The sequence data described in this paper have been submitted to the GenBank data library under accession nos.U96944–U96962 and S87165.]

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“…É o caso dos alelos do próprio gene do AR, que exibe de 40 a 62 repetições CAG no amino-terminal e causam a doença de Kennedy, uma síndrome neuromuscular degenerativa com insensibilidade ao andrógeno. Também são conhecidos os alelos dos genes responsáveis pela doença de Huntington, pela ataxia espinocerebelar tipo 1, pela doença de Machado-Joseph e pela síndrome do X frágil, que manifestam desde algumas dezenas até milhares de trinucleotídeos CAG ou GGG (47). Certos alelos do gene SRD5A2, responsável pela síntese isoenzima tipo II da 5a redutase expressa na próstata, também contêm repetições de dinucleotídeos (TA) n na região 3' o que parece elevar a atividade da enzima, o nível de DHT na próstata e, consequentemente, os riscos de desenvolver alguns tipos de câncer prostático (48,49).…”

Section: O Receptor De Andrógenosunclassified

Fatores hormonais e genéticos na próstata normal e neoplásica

Carvalho-Salles¹,

Tajara²

1999

Arq Bras Endocrinol Metab

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Recently, a great deal of attention has focused on the growth regulatory effects of androgens in prostate cells. This has also resulted in much interest in the role of these steroid hormones in the development and maintenance of both normal and neoplastic prostate. However, it has not been possible to identify the exact relationship between androgenic hormone levels and the risk of this disease. The hormone-androgen receptor complex, by association with the DNA androgen response elements, specifically promotes the growth of the prostate gland. It has been recognized that there is a close relationship between the androgen mediated signaling pathway and those promoted by peptide growth factors. More insights are being gained into these complex interactions, some of which may lead to novel therapeutic maneuvers. (Arq Bras Endocrinol Metab 1999;43/3: 177-185).Keywords: Prostate; Prostatic neoplasia; Androgens; Growth factors; Therapy. CONSIDERAÇÕES GERAISA PRÓSTATA É UM ÓRGÃO FIRME, de consistência fibroclástica, que pesa cerca de 20 gramas e apresenta diâmetros máximos de 40 mm. Está localizada na base da bexiga urinaria e, do ponto de vista anatômico, pode ser dividida em lobos laterais, anterior, posterior e mediano. Essa divisão somente é nítida no período embrionário e, no órgão adulto, o limite entre os lobos é impreciso, não existindo septos de tecido conjuntivo que os separem. Histologicamente, apresenta dois tipos glandulares, tubuloacinosas compostas e ramificadas, cuja secreção tem como principal função manter

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DNA-Triplet Repeats and Neurologic Disease

Cited by 36 publications

References 25 publications

Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo

Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo

The Complex Mutation Pattern of a Microsatellite

Fatores hormonais e genéticos na próstata normal e neoplásica

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