About: ß-Thalassemia Due to Intronic LINE-1 Insertion in the ß-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the ß-GlobinL1 Allele     Goto   Sponge   NotDistinct   Permalink

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Description
  • We describe the molecular etiology of ß(+) -thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the ß-globin gene (HBB). The transcript level of the affected ß-globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed ß-globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the ß-globinL1 allele also resulted from a reduced rate of transcription and decreased production of full-length ß-globin primary transcripts. The promoter and enhancer sequences of the ß-globinL1 allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the ß-globinL1 transcription despite permanent ß-globinL1 promoter CpG methylation. This result indicates that the decreased rate of transcription from the ß-globinL1 allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the ß-globin gene represents a novel etiology of ß-thalassemia.
  • We describe the molecular etiology of ß(+) -thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the ß-globin gene (HBB). The transcript level of the affected ß-globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed ß-globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the ß-globinL1 allele also resulted from a reduced rate of transcription and decreased production of full-length ß-globin primary transcripts. The promoter and enhancer sequences of the ß-globinL1 allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the ß-globinL1 transcription despite permanent ß-globinL1 promoter CpG methylation. This result indicates that the decreased rate of transcription from the ß-globinL1 allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the ß-globin gene represents a novel etiology of ß-thalassemia. (en)
Title
  • ß-Thalassemia Due to Intronic LINE-1 Insertion in the ß-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the ß-GlobinL1 Allele
  • ß-Thalassemia Due to Intronic LINE-1 Insertion in the ß-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the ß-GlobinL1 Allele (en)
skos:prefLabel
  • ß-Thalassemia Due to Intronic LINE-1 Insertion in the ß-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the ß-GlobinL1 Allele
  • ß-Thalassemia Due to Intronic LINE-1 Insertion in the ß-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the ß-GlobinL1 Allele (en)
skos:notation
  • RIV/61989592:15110/13:33144967!RIV14-MZ0-15110___
http://linked.open...avai/predkladatel
http://linked.open...avai/riv/aktivita
http://linked.open...avai/riv/aktivity
  • P(EE2.3.30.0041), P(NT11208), P(NT13587), S
http://linked.open...iv/cisloPeriodika
  • 10
http://linked.open...vai/riv/dodaniDat
http://linked.open...aciTvurceVysledku
http://linked.open.../riv/druhVysledku
http://linked.open...iv/duvernostUdaju
http://linked.open...titaPredkladatele
http://linked.open...dnocenehoVysledku
  • 107977
http://linked.open...ai/riv/idVysledku
  • RIV/61989592:15110/13:33144967
http://linked.open...riv/jazykVysledku
http://linked.open.../riv/klicovaSlova
  • ß-thalassemia; ß-globin; epigenetic repression; LINE-1; HBB (en)
http://linked.open.../riv/klicoveSlovo
http://linked.open...odStatuVydavatele
  • US - Spojené státy americké
http://linked.open...ontrolniKodProRIV
  • [44F4C908056F]
http://linked.open...i/riv/nazevZdroje
  • Human Mutation
http://linked.open...in/vavai/riv/obor
http://linked.open...ichTvurcuVysledku
http://linked.open...cetTvurcuVysledku
http://linked.open...vavai/riv/projekt
http://linked.open...UplatneniVysledku
http://linked.open...v/svazekPeriodika
  • 34
http://linked.open...iv/tvurceVysledku
  • Indrák, Karel
  • Kučerová, Jana
  • Divoká, Martina
  • Divoký, Vladimír
  • Prchal, Josef T.
  • Láníková, Lucie
  • Issa, Jean-Pierre
  • Papayannopoulou, Thalia
http://linked.open...ain/vavai/riv/wos
  • 000324752700008
issn
  • 1059-7794
number of pages
http://bibframe.org/vocab/doi
  • 10.1002/humu.22383
http://localhost/t...ganizacniJednotka
  • 15110
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