Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.

Liebhaber, Stephen A.; Griese, Ernst-Ulrich; Weiss, Ingrid M.; Cash, F E; Ayyub, Helena; Higgs, Douglas R.; Horst, J.

doi:10.1073/pnas.87.23.9431

Cited by 58 publications

(27 citation statements)

References 39 publications

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“…In the remaining cases, the mechanism has not yet been established. However, it is interesting that some (e.g., [aa] IJ , [aa] Sco ) (Liebhaber et al 1990;Viprakasit et al 2003), but not all, of these mutations appear to have arisen de novo, because neither parent has the abnormal chromosome.…”

Section: Deletions Removing the Upstream Regulatory Elements Of The Amentioning

confidence: 99%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

125

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The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the a-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases.

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Section: Deletions Removing the Upstream Regulatory Elements Of The Amentioning

confidence: 99%

The Molecular Basis of -Thalassemia

Higgs

2013

Cold Spring Harbor Perspectives in Medicine

125

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“…Naturally occurring deletions of sequences upstream of either globin gene cluster down-regulate globin gene expression, suggesting that major regulatory sequences lie in these regions (3)(4)(5)(6)(7)(8). This was confirmed initially in the /3 cluster, where the upstream locus control region (,3-LCR), marked by the presence of four DNase I-hypersensitive sites (HSs) (9)(10)(11), was shown to be essential for high-level, tissuespecific expression of the human ,B gene in transgenic mice.…”

mentioning

confidence: 99%

Analysis of the human alpha-globin gene cluster in transgenic mice.

Sharpe

Wells

Whitelaw

et al. 1993

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

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A 350-bp segment of DNA associated with an erythroid-specific DNase I-hypersensitive site (HS -40), upstream of the a-globin gene cluster, has been identified as the major tissue-specific regulator of the a-globin genes. However, this element does not direct copy number-dependent or developmentally stable expression of the human genes in transgenic mice. To determine whether additional upstream hypersensitive sites could provide more complete regulation of a gene expression we have studied 17 lines of transgenic mice bearing various DNA fragments containing HSs -33, -10, -8, and -4, in addition to HS -40. Position-independent, high-level expression of the human C-and a-globin genes was consistently observed in embryonic erythroid cells. However, the additional HSs did not confer copy-number dependence, alter the level of expression, or prevent the variable down-regulation of expression in adults. These results suggest that the region upstream of the human a-globin genes is not equivalent to that upstream of the f3 locus and that although the two clusters are coordinately expressed, there may be differences in their regulation.

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“…To explore the mechanisms which regulate message stability, we developed a transient transfection system that could be used in conjunction with a reverse transcription-PCR (RT-PCR)-based assay to measure the impact of mutations on stability of the ␣2-globin mRNA (31,52,53). Initial studies focused on examining the defect in expression of a naturally occurring ␣2-globin mutant called Constant Spring (CS).…”

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confidence: 99%

Erythroid Cell-Specific mRNA Stability Elements in the α2-Globin 39 Nontranslated Region

Weiss

Liebhaber

1995

Molecular and Cellular Biology

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161

163

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Very little is known about the mechanisms mediating longevities of mRNAs. As a means of identifying potential cis-and trans-acting elements which stabilize an individual mRNA, naturally occurring mutations that decreased stability of the normally long-lived globin mRNA were analyzed. Our previous studies demonstrated that a subset of mutations which allowed the translating ribosome to read through into the ␣2-globin 3 nontranslated region (NTR) targeted the mutant mRNAs for accelerated turnover in erythroid cells but not in several nonerythroid cell lines (I. M. Weiss and S. A. Liebhaber, Mol. Cell. Biol. 14:8123-8132, 1994). These results suggested that translational readthrough interfered with some feature of the ␣2-globin 3 NTR required for message stability in erythroid cells. To define the cis-acting sequences which comprise this erythroid cell-specific stability determinant, scanning mutagenesis was performed on the ␣2-globin 3 NTR, and the stability of each mutant mRNA was examined during transient expression. Three cytidine-rich regions which are required for longevity of the ␣2-globin mRNA were identified. However, in contrast to the readthrough mutations, base substitutions in these elements destabilize the message through a translation-independent mechanism. To account for these results, we propose that the cis-acting elements form a complex or determinant in the normal ␣2-globin mRNA which protects the message from degradation in erythroid cells. Disruption of this determinant, by translational readthrough or because mutations in an element prevent or inhibit its formation, targets the message for accelerated turnover in these cells.

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Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster.

Cited by 58 publications

References 39 publications

The Molecular Basis of -Thalassemia

The Molecular Basis of -Thalassemia

Analysis of the human alpha-globin gene cluster in transgenic mice.

Erythroid Cell-Specific mRNA Stability Elements in the α2-Globin 39 Nontranslated Region

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