The G→A Mutation at Position +22 3<sup>1</sup>to the Cap Site of the β-Globin Gene as a Possible Cause for a β-Thalassemia

Öner, Reyhan; Agarwal, Sarita; Dimovski, Aleksandar; Ефремов, Г. Д.; Petkov, G.; Altay, Çiğdem; Gürgey, Aytemiz; Huisman, T. H. J.

doi:10.3109/03630269109072485

Cited by 55 publications

(31 citation statements)

References 20 publications

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“…We found 11 additional mutations ( Table 2) that were detected by resequencing in known disease-related genes in affected patients (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). These uORF-altering mutations were not present in population controls (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), and were either the sole mutation detected in the sequenced exons, or were compound heterozygous with a missense/nonsense mutation ( Table 2). The patient presentation was consistent with a recessive phenotype in 3 of the 4 compound heterozygous cases (37, 38, 42, 43), and was ambiguous …”

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confidence: 98%

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Calvo

Pagliarini

Mootha

2009

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

798

899

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Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the 5 UTR that is out-of-frame with the main coding sequence. Although uORFs are present in approximately half of human and mouse transcripts, no study has investigated their global impact on protein expression. Here, we report that uORFs correlate with significantly reduced protein expression of the downstream ORF, based on analysis of 11,649 matched mRNA and protein measurements from 4 published mammalian studies. Using reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30 -80%, with a modest impact on mRNA levels. We additionally identify polymorphisms that alter uORF presence in 509 human genes. Finally, we report that 5 uORF-altering mutations, detected within genes previously linked to human diseases, dramatically silence expression of the downstream protein. Together, our results suggest that uORFs influence the protein expression of thousands of mammalian genes and that variation in these elements can influence human phenotype and disease.polymorphism ͉ post-transcriptional control ͉ proteomics ͉ translation ͉ uORF

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mentioning

confidence: 98%

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Calvo

Pagliarini

Mootha

2009

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

798

899

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“…However, a TAF9-independent mode of KLF1 activation is seen at the alpha-hemoglobin stabilizing protein (AHSP) gene, which does not contain a discernible DPE. Together, these interactions with general transcription components are of critical importance for ␤-globin expression, since mutation within TFIIH leads to ␤-thalassemia (26), and some ␤-thalassemia mutations map to the ␤-globin DPE (27,28).…”

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confidence: 99%

EKLF/KLF1, a Tissue-Restricted Integrator of Transcriptional Control, Chromatin Remodeling, and Lineage Determination

Yien

Bieker

2013

Molecular and Cellular Biology

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Erythroid Krüppel-like factor (EKLF or KLF1) is a transcriptional regulator that plays a critical role in lineage-restricted control of gene expression. KLF1 expression and activity are tightly controlled in a temporal and differentiation stage-specific manner. The mechanisms by which KLF1 is regulated encompass a range of biological processes, including control of KLF1 RNA transcription, protein stability, localization, and posttranslational modifications. Intact KLF1 regulation is essential to correctly regulate erythroid function by gene transcription and to maintain hematopoietic lineage homeostasis by ensuring a proper balance of erythroid/megakaryocytic differentiation. In turn, KLF1 regulates erythroid biology by a wide variety of mechanisms, including gene activation and repression by regulation of chromatin configuration, transcriptional initiation and elongation, and localization of gene loci to transcription factories in the nucleus. An extensive series of biochemical, molecular, and genetic analyses has uncovered some of the secrets of its success, and recent studies are highlighted here. These reveal a multilayered set of control mechanisms that enable efficient and specific integration of transcriptional and epigenetic controls and that pave the way for proper lineage commitment and differentiation.

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“…Boxed sequences, arrows, and numbering indicate positions of deleterious mutations in each promoter (panels A and C and reference 43). Bases in red indicate the positions of known ␤-thalassemia point mutations in the human ␤-globin promoter (2,8,24,31,57,90), except for ϩ13 (13). Blue-colored bases indicate the sequences representing DCE subelements.…”

Section: Resultsmentioning

confidence: 99%

Functional Characterization of Core Promoter Elements: the Downstream Core Element Is Recognized by TAF1

Lee¹,

Gershenzon

Gupta³

et al. 2005

Molecular and Cellular Biology

101

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Downstream elements are a newly appreciated class of core promoter elements of RNA polymerase IItranscribed genes. The downstream core element (DCE) was discovered in the human ␤-globin promoter, and its sequence composition is distinct from that of the downstream promoter element (DPE). We show here that the DCE is a bona fide core promoter element present in a large number of promoters and with high incidence in promoters containing a TATA motif. Database analysis indicates that the DCE is found in diverse promoters, supporting its functional relevance in a variety of promoter contexts. The DCE consists of three subelements, and DCE function is recapitulated in a TFIID-dependent manner. Subelement 3 can function independently of the other two and shows a TFIID requirement as well. UV photo-cross-linking results demonstrate that TAF1/TAF II 250 interacts with the DCE subelement DNA in a sequence-dependent manner. These data show that downstream elements consist of at least two types, those of the DPE class and those of the DCE class; they function via different DNA sequences and interact with different transcription activation factors. Finally, these data argue that TFIID is, in fact, a core promoter recognition complex.Promoters transcribed by RNA polymerase II are complex and composed of different classes of elements, one of which consists of the core promoter elements represented by the TATA box, the TFIIB response elment (BRE), the initiator, the downstream promoter element (DPE), and other newly recognized elements (reviewed in reference 73). One view of core promoters is that they are fairly ubiquitous and that they play only a trivial role in transcriptional regulation. According to this view, the uniqueness and specificity inherent in a promoter derive from the various DNA binding activators and coactivators that recognize the regulatory elements usually located upstream of the TATA box and/or initiator. The small number of core promoter elements and their apparent lack of diversity compared to that of the staggering numbers of activators have supported such a view. Also contributing to this view is the fact that core promoters have been rather poorly studied in their natural context, and thus, regulatory phenomena may have been missed.Yet there are a few examples where the core promoter apparently plays a very specific role. Early examples include studies of the myoglobin and simian virus 40 TATA boxes (86) and the hsp70 TATA box (72) that indicated a requirement for TATA boxes of a particular sequence. The TdT promoter was also shown to become inactive upon the inclusion of a TATA box (20). Lastly, some activators display preferences for particular core promoter architectures (7,18,56).This perception of core promoters lacking diversity is being revised with the findings of other core promoter elements such as the BRE (41) and elements located downstream of the transcriptional start site such as the DPE (5, 6, 40, 89), the downstream core element (DCE) (43), and the motif 10 element (MTE) (48). The mo...

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The G→A Mutation at Position +22 3¹to the Cap Site of the β-Globin Gene as a Possible Cause for a β-Thalassemia

Cited by 55 publications

References 20 publications

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

EKLF/KLF1, a Tissue-Restricted Integrator of Transcriptional Control, Chromatin Remodeling, and Lineage Determination

Functional Characterization of Core Promoter Elements: the Downstream Core Element Is Recognized by TAF1

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The G→A Mutation at Position +22 31to the Cap Site of the β-Globin Gene as a Possible Cause for a β-Thalassemia

Cited by 55 publications

References 20 publications

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

EKLF/KLF1, a Tissue-Restricted Integrator of Transcriptional Control, Chromatin Remodeling, and Lineage Determination

Functional Characterization of Core Promoter Elements: the Downstream Core Element Is Recognized by TAF1

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The G→A Mutation at Position +22 3¹to the Cap Site of the β-Globin Gene as a Possible Cause for a β-Thalassemia