Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites.

Driscoll, Monica; Dobkin, Carl; Alter, Blanche P.

doi:10.1073/pnas.86.19.7470

Cited by 223 publications

(91 citation statements)

References 32 publications

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“…The LCR has historically been characterized by clinical observations and by additional genetic approaches. Deletions of this region in humans are associated with forms of b-thalassemia, [20][21][22] where the b-globin gene, despite absence of mutations, was inactivated. 23,24 Further characterization of this region, by the use of transgenic animals, indicated that the LCR is absolutely required for high level of expression of the b-globin gene in erythroid cells.…”

Section: Globin Synthesis Erythropoiesis and Iron Metabolism: A Compmentioning

confidence: 99%

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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b-thalassemias are monogenic disorders characterized by defective synthesis of the b-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the b-globin gene or its regulatory elements have been associated with b-thalassemias. Due to the complexity of the regulation of the b-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of b-globin and abnormal erythropoiesis, as well as current and novel therapies. ABSTRACTThe complex phenotype of b-thalassemias b-thalassemias are monogenic disorders characterized by reduced or no synthesis of the b-globin chain, one of the major components of adult hemoglobin (HbA). Several hundred mutations in the b-globin gene or regulatory elements have been associated with b-thalassemias.

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Section: Globin Synthesis Erythropoiesis and Iron Metabolism: A Compmentioning

confidence: 99%

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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“…The LCR has been shown by studies of natural deletions of ␥␦␤-thalassemia (8,11,24) and by gene transfer experiments (14,18,20,51) to be indispensable for erythroid-cell-specific and high-level transcription of cis-linked globin genes and transgenes. The mechanism by which the LCR regulates transcription of the distant embryonic ε-, fetal ␥-, and adult ␤-globin genes at the respective developmental stages is not fully understood.…”

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confidence: 99%

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

Kong

Bohl

et al. 1997

Molecular and Cellular Biology

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The locus control region (LCR) of the human ␤-globin gene domain is defined by four erythroid-cell-specific DNase I-hypersensitive (HS) sites, HS1, -2, -3, and -4, located 50 to 70 kb upstream of the ␤-globin gene in a transcriptional direction: 5Ј HS4-HS3-HS2-HS1-//-ε-G ␥-A ␥-␦-␤ 3Ј (17,20,37,50). The LCR has been shown by studies of natural deletions of ␥␦␤-thalassemia (8,11,24) and by gene transfer experiments (14,18,20,51) to be indispensable for erythroid-cell-specific and high-level transcription of cis-linked globin genes and transgenes. The mechanism by which the LCR regulates transcription of the distant embryonic ε-, fetal ␥-, and adult ␤-globin genes at the respective developmental stages is not fully understood.In previous studies examining the mechanism of LCR function, a number of laboratories have investigated the ability of the individual HS sites to activate the transcription of cislinked genes in cell lines and transgenic mice. Among the LCR HS sites, HS2 has been found to possess developmental-stageindependent enhancer function (52). It is capable of stimulating the transcription of embryonic ε-, fetal ␥-, and adult ␤-globin genes in erythroid cells at the corresponding developmental stages (9,28,34,42,45,47) and may therefore constitute a major functional component of the LCR. However, a recent targeted deletion study shows that deletion of the HS2 enhancer from the murine LCR generated only mild effects on the expression of the ␤-like globin genes (15), suggesting that HS2 is not essential for LCR function and that LCR function may be due to the contribution of the other HS sites. Surprisingly, similar targeted deletion of HS3 also did not cause significant changes in the expression of the ␤-like globin genes (22). These findings suggest that LCR function is due not to the contribution of any specific HS site but to a series of interactions among its functional components, including the enhancer elements underlying the HS sites.In the above-described targeted deletion studies, deleting the HS2 or the HS3 sequence from the endogenous murine LCR and inserting in its place an independent transcription unit-a neomycin-resistant gene driven by a strong promoter-has been found to disrupt LCR function and cause severe anemia in and the deaths of homozygous transgenic mice (15,21). In the human ␤-LCR, inserting an independent transcription unit at a location between the HS2 enhancer and the downstream globin genes also disrupted LCR function (23) and caused the distantly downstream ␤-globin gene to be transcriptionally turned off. The mechanism by which the transcription of a foreign gene within the LCR might disrupt LCR function is not clearly understood (21).In an attempt to delineate the functional mechanism of the HS2 enhancer and ultimately of the LCR, we have previously analyzed the transcriptional status of the HS2 enhancer in transfected recombinant chloramphenicol acetyltransferase (CAT) plasmids (53). This earlier study showed that the transfected HS2 enhancer is itself transcribed in eryt...

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“…There are, however, a few precedents of disease-causing mutations affecting regulatory DNA elements of human genes. Such sequences may include promoter regions (5,6), other sequences within introns or outside the gene that are important for its expression (7), or a tightly linked gene that serves as a transcription factor required for gene expression (8).…”

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confidence: 99%

A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.

Koivisto

Palvimo

Jänne

et al. 1994

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

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Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites.

Cited by 223 publications

References 32 publications

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

Transcription of the HS2 Enhancer toward a cis-Linked Gene Is Independent of the Orientation, Position, and Distance of the Enhancer Relative to the Gene

A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.

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