Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster

Hatton, Chris; Wilkie, Andrew; Drysdale, H. C.; Wood, W. G.; Vickers, Mark A.; Sharpe, Jacqueline A.; Ayyub, Helena; Pretorius, I M; Buckle, VJ; Higgs, Douglas R.

doi:10.1182/blood.v76.1.221.221

Cited by 103 publications

(22 citation statements)

References 37 publications

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“…They are co‐ordinately regulated by the 350‐bp major regulatory element (αMRE), better known as HS‐40, located upstream of the structural genes (Forrester et al , 1987; Grosveld et al , 1987; Higgs et al , 1990). The importance of these sequences became evident from large deletions that occurred upstream of the structural genes which abolished the globin gene expression in cis (Hatton et al , 1990; Liebhaber et al , 1990; Wilkie et al , 1990; Romao et al , 1991, 1992). Genomic footprinting has demonstrated the formation in vivo of specific nuclear factor DNA complexes at a subset of these sequence motifs in erythroid cells (Fig 1) (Strauss et al , 1992).…”

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confidence: 99%

Genetic polymorphism of the major regulatory element HS‐40 upstream of the human α‐globin gene cluster

et al. 2002

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Summary. The highly conserved 350-bp major regulatory element HS-40 (or aMRE) upstream of the human a-globin gene cluster is involved in the regulation of a-globin gene expression. The study of aMRE differences between human populations and the evolution of aMRE sequences in mammals may lead to a better understanding of the function and importance of this element in the regulation of expression of the downstream a-cluster. Denaturing gradient gel electrophoresis was used to determine the sequence heterogeneity of the aMRE region in 276 unrelated individuals, representing seven different populations. Furthermore, we analysed the a major regulatory elements of chimpanzee, orang-utan and rhesus monkeys and compared them with the equivalent human and murine sequences. Six different aMRE haplotypes (labelled A to F) were found in humans. Haplotype frequencies between the seven populations showed a gradual shift to a higher haplotype A distribution from west to east, being the highest in Indonesians. The African sample shows the largest divergence in haplotypes. Five out of six different haplotypes were present, three of which were exclusively found in Africans. The high prevalence of the haplotype A in humans, together with the conservation of this haplotype in apes, suggests that it is the ancestral one. The aMRE fragment appears to be a highly polymorphic marker, which could be used in combination with the regular markers in the a-cluster to extend the haplotype and to follow segregation of a-thalassaemia genes in population studies more accurately.

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confidence: 99%

Genetic polymorphism of the major regulatory element HS‐40 upstream of the human α‐globin gene cluster

et al. 2002

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“…Previous work has also shown that genes are deregulated in cells of ATR-X patients and ATRX mutant mice [203,204]. Two possible mechanisms by which ATRX can act as a transcriptional regulator have been demonstrated [193,205].…”

Section: Alpha-thalassemia Mental Retardation X-linked Syndrome (Atr-x)mentioning

confidence: 97%

Chromatin Structure and Intellectual Disability Syndromes

Elbert¹,

Bérubé²

2013

Developmental Disabilities - Molecules Involved, Diagnosis, and Clinical Care

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“…Thalassaemias are characterized by inherited mutations leading to a reduction of the synthesis of α- (α-thalassaemia) or β-globin (β-thalassaemia) chains from one allele. Human genetics is a good approach to identify functional remote regulatory elements, and original observations were made in patients with α- and β-thalassaemia [22] – [24] . In most cases, a deletion removing a globin gene is the cause of this down-regulation, but in some rare cases, the genes (including their promoters) remain intact [25] .…”

Section: Structure Of the α-Globin Locusmentioning

confidence: 99%

“…Due to the nature of the disease (anaemia), it was however difficult to perform a number of experiments on primary cells because of the large amount of material required and also because this material is only available for a limited time. For this reason, interspecific hybrids were produced by the fusion of a human immortalised B cell (Epstein-Barr virus [EBV] infected) with the mouse MEL cell line described earlier [24] , [28] , [64] , [65] .…”

Section: Role(s) Of the Remote Regulatory Sequencesmentioning

confidence: 99%

Uncovering Enhancer Functions Using the α-Globin Locus

Vernimmen

2014

PLoS Genet

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Over the last three decades, studies of the α- and β-globin genes clusters have led to elucidation of the general principles of mammalian gene regulation, such as RNA stability, termination of transcription, and, more importantly, the identification of remote regulatory elements. More recently, detailed studies of α-globin regulation, using both mouse and human loci, allowed the dissection of the sequential order in which transcription factors are recruited to the locus during lineage specification. These studies demonstrated the importance of the remote regulatory elements in the recruitment of RNA polymerase II (PolII) together with their role in the generation of intrachromosomal loops within the locus and the removal of polycomb complexes during differentiation. The multiple roles attributed to remote regulatory elements that have emerged from these studies will be discussed.

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Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster

Abstract: We describe a family in which a-thalassemia occurs in association with a deletion of 62 kilobases from a region RNA analysis.

Cited by 103 publications

References 37 publications

Genetic polymorphism of the major regulatory element HS‐40 upstream of the human α‐globin gene cluster

Genetic polymorphism of the major regulatory element HS‐40 upstream of the human α‐globin gene cluster

Chromatin Structure and Intellectual Disability Syndromes

Uncovering Enhancer Functions Using the α-Globin Locus

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