A novel silent β‐thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF

Moi, Paolo; Faà, V.; Marini, Maria Giuseppina; Asunis, Isadora; Ibba, Giuseppe; Cao, Antonio; Rosatelli, C

doi:10.1111/j.1365-2141.2004.05146.x

Cited by 37 publications

(25 citation statements)

References 13 publications

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“…A C ! G transversion has also been reported in the same 2101 position and heterozygotes have a "silent" phenotype (Moi et al 2004). Several other mutations in the 5 0 and 3 0 UTRs are also "silent" (Table 1).…”

Section: Variants Of B-thalassemiamentioning

confidence: 95%

The Molecular Basis of -Thalassemia

Thein

2013

Cold Spring Harbor Perspectives in Medicine

302

189

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The b-thalassemias are characterized by a quantitative deficiency of b-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural b gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most b-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of b-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of b-thalassemia has provided a paradigm for understanding of much of human genetics.

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Section: Variants Of B-thalassemiamentioning

confidence: 95%

The Molecular Basis of -Thalassemia

Thein

2013

Cold Spring Harbor Perspectives in Medicine

302

189

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“…The number of disease mutations in cis-regulatory regions is rapidly increasing due to the advent of high-density single nucleotide polymorphism detection and next-generation sequencing technology (15). For some DNA variants identified, such as those that alter either the conserved TATA box (3) or the binding site for the erythroid Kruppel-like transcription factor (29) in the human ␤-globin promoter, the association with the disease (␤-thalassemia) with the causative variant is relatively easy to demonstrate. Other variations, such as the variant that creates a GATA-1 binding site that causes ␣-thalassemia by recruiting the transcriptional machinery away from the ␣-globin genes (11), are more complex and require both genomic and functional analysis to prove they are the causative mutations.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of a Novelcis-Acting Regulatory Region within the Human Ankyrin Gene (ANK-1) Promoter

Laflamme

Owen

Devlin

et al. 2010

Molecular and Cellular Biology

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The characterization of atypical mutations in loci associated with diseases is a powerful tool to discover novel regulatory elements. We previously identified a dinucleotide deletion in the human ankyrin-1 gene (ANK-1) promoter that underlies ankyrin-deficient hereditary spherocytosis. The presence of the deletion was associated with a decrease in promoter function both in vitro and in vivo establishing it as a causative hereditary spherocytosis mutation. The dinucleotide deletion is located in the 5 untranslated region of the ANK-1 gene and disrupts the binding of TATA binding protein and TFIID, components of the preinitiation complex. We hypothesized that the nucleotides surrounding the mutation define an uncharacterized regulatory sequence. To test this hypothesis, we generated a library of more than 16,000 ANK-1 promoters with degenerate sequence around the mutation and cloned the functional promoter sequences after cell-free transcription. We identified the wild type and three additional sequences, from which we derived a consensus. The sequences were shown to be functional in cell-free transcription, transient-transfection, and transgenic mouse assays. One sequence increased ANK-1 promoter function 5-fold, while randomly chosen sequences decreased ANK-1 promoter function. Our results demonstrate a novel functional motif in the ANK-1 promoter.Hereditary spherocytosis (HS; OMIM 182900) is a dominant inherited hemolytic anemia that affects approximately 1/2,500 people of all races worldwide (1, 17, 18). Typically, HS patients have mild symptoms, which can be exacerbated by viral infections (19). These symptoms include elevated reticulocyte counts and smaller, spherical erythrocytes on a blood smear and are accompanied by an abnormal osmotic fragility (13,19,23). The majority of HS mutations have been found in the genes encoding the erythrocyte membrane skeleton proteins ankyrin-1 (ANK-1; ϳ60%) and Band 3 (SLC4A1; ϳ20%) (1,19). Virtually all of the described HS mutations cause a functional deficiency of erythrocyte skeleton proteins, either by premature termination and/or amino acid substitutions in regions critical for the protein-protein interactions that stabilize the erythrocyte membrane skeleton (17, 18). In the 10 to 20% of patients in whom no mutations have been detected in the coding region of the membrane skeleton protein genes, the causative mutations are proposed to be in cis-acting regulatory regions resulting in decreased transcription of mRNA resulting in haploinsufficiency (12,17,18).Support for this hypothesis has come from our previous analysis of a German patient with a severe form of HS (20). The patient was shown to have two mutations in the ANK-1 gene. The first was a 20-bp deletion in exon 6, leading to premature termination, presumably inherited from the father. The second mutation was a deletion of a TG dinucleotide in the 5Ј untranslated region of the ANK-1 gene located at position Ϫ72/73 relative to the ATG initiation codon (12,20) or ϩ 12/13 from the transcriptional start site (TSS) ...

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“…Individuals who inherit this single β thalassaemia allele, either β° or β + have thalassaemia trait. Moi et al, (2004) This condition, β thalassaemia major will normally present with profound anaemia requiring regular blood transfusion without which the patient may die within the first 2 years of life. Inheritance of two β thalassaemia alleles, however, does not always lead to thalassaemia major and many patients with two β thalassaemia alleles have a milder disease, ranging from a condition that is slightly less severe than transfusion-dependence to one that is asymptomatic and often mistaken for β thalassaemia trait (Thein, 2001).…”

Section: Beta (β)-Thalassaemiamentioning

confidence: 99%

“…The diverse collection of phenotypes between the two extremes of β thalassaemia major and β thalassaemia trait constitute the clinical syndrome of β thalassaemia intermedia (Moi, et al, 2004). No β-or δ-chain but increased γ-chain production (Adapted from Babior and Stossel 1994)…”

Section: Beta (β)-Thalassaemiamentioning

confidence: 99%

An investigation of the protective effect of alpha+‐thalassaemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana

Opoku-Okrah

Gordge

Nakua

et al. 2013

Int J Lab Hematology

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This is an electronic version of a PhD thesis awarded by the University of Westminster. © The Author, 2012. This is an exact reproduction of the paper copy held by the University of Westminster library.The WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profit-making enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch: (http://westminsterresearch.wmin.ac.uk/).In case of abuse or copyright appearing without permission email repository@westminster.ac.uk

show abstract

A novel silent β‐thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF

Cited by 37 publications

References 13 publications

The Molecular Basis of -Thalassemia

The Molecular Basis of -Thalassemia

Functional Analysis of a Novelcis-Acting Regulatory Region within the Human Ankyrin Gene (ANK-1) Promoter

An investigation of the protective effect of alpha+‐thalassaemia against severe Plasmodium falciparum amongst children in Kumasi, Ghana

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