The modifying effect of Xmn1-HBG2 on thalassemic phenotype is associated with its linked elements in the beta globin locus control region, including the palindromic site at 5′HS4

Neishabury, Maryam; Zamani, Shahbaz; Azarkeivan, Azita; Abedini, Seyedeh Sedigheh; Darvish, Hossein; Zamani, Fahimeh; Najmabadi, Hossein

doi:10.1016/j.bcmd.2011.10.001

Cited by 10 publications

(6 citation statements)

References 24 publications

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“…Al-though changes in proteomic expression in disease-specific contexts have been well characterized in the literature and mentioned previously in this paper, identification of expression changes in age-specific contexts is a potentially powerful tool for clinical use. For example, blood borne pathologies such as beta-thalassemias and other related conditions often feature prolonged gamma chain HBG2 production, long into early childhood (24). Thus, proteomic analysis of patient plasma, in reference to age-specific protein reference ranges, may assist clinicians in the diagnostic phase, or help to elucidate the severity of the relevant pathology.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Bjelosevic

Pascovici

Peng

et al. 2017

Molecular & Cellular Proteomics

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Human blood plasma is a complex biological fluid containing soluble proteins, sugars, hormones, electrolytes, and dissolved gasses. As plasma interacts with a wide array of bodily systems, changes in protein expression, or the presence or absence of specific proteins are regularly used in the clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. In this study, we utilized SWATH-MS to identify and quantify proteins in the blood plasma of healthy neonates, infants under 1 year of age, children between 1-5 years, and adults. We identified more than 100 proteins that showed significant differential expression levels across these age groups, and we analyzed variation in protein expression across the age spectrum. The plasma proteomic profiles of neonates were strikingly dissimilar to the older children and adults. By extracting the SWATH data against a large human spectral library we increased protein identification more than 6-fold (940 proteins) and confirmed the concentrations of several of these using ELISA. The results of this study map the variation in expression of proteins and pathways often implicated in disease, and so have significant clinical implication.

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Section: Discussionmentioning

confidence: 99%

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Bjelosevic

Pascovici

Peng

et al. 2017

Molecular & Cellular Proteomics

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“…The Xmn1-HBG2 site is essential because of its considerable impact on trait variance and its high frequency (∼30%) in most population groups, including Europeans, Africans, and Asian Indians. [ 33 ] Although increases in HbF and F cells associated with Xmn1-HBG2 are minimal or undetectable in healthy adults, clinical studies have shown that under conditions of stress, erythropoiesis in homozygous β-thalassemia, the presence of Xmn1-HBG2 leads to a much higher HbF response associated with a delayed transfusion need. This could explain why the same mutation on different ß-chromosomal backgrounds, some with others without the Xmn1-HBG2 variant, is associated with different clinical severities.…”

Section: Resultsmentioning

confidence: 99%

Molecular genetics of β-thalassemia

et al. 2021

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β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the α-globin genotype provides some prediction of disease severity for β-thalassemia. However, the generation of an additive composite genetic risk score predicts prognosis, and guide management requires a larger panel of genetic modifiers yet to be discovered.Presently, using data from prior clinical trials guides the design of further research and academic studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene therapy approaches.Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. In addition to these HBB mutation-independent strategies involving HbF synthesis de-repression, the expanding genome editing toolkit provides increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin restoration for personalized treatment of hemoglobinopathies. Allogeneic hematopoietic stem cell transplantation was, until very recently, the curative option available for patients with transfusion-dependent β-thalassemia. Gene therapy currently represents a novel therapeutic promise after many years of extensive preclinical research to optimize gene transfer protocols.We summarize the current state of developments in the molecular genetics of β-thalassemia over the last decade, including the mechanisms associated with ineffective erythropoiesis, which have also provided valid therapeutic targets, some of which have been shown as a proof-of-concept.

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“…The −158C > T (rs7482144) SNP located at the Xmn I site of the HBG2 (hemoglobin gamma G gene) promoter in the HBB locus was shown to be correlated with HbF levels in pioneering studies conducted on normal individuals and patients with sickle cell disease or β-thalassemia [24] , [25] , [26] , [27] . In the absence of a demonstrated functional role for this site, it has been suggested that HbF phenotype is modified by cis -linked elements located elsewhere in the β-globin cluster and in linkage disequilibrium with this SNP [28] , [29] . Indeed, a quasi-palindromic structure located at the 5′ DNAse hypersensitive site 4 (HS4) of the locus control region (LCR), a polymorphism of which is in linkage disequilibrium with the Xmn I site [28] , may affect direct or indirect interactions with the transcriptional repressor BCL11A [30] .…”

Section: Pharmacological Therapiesmentioning

confidence: 99%

“…In the absence of a demonstrated functional role for this site, it has been suggested that HbF phenotype is modified by cis -linked elements located elsewhere in the β-globin cluster and in linkage disequilibrium with this SNP [28] , [29] . Indeed, a quasi-palindromic structure located at the 5′ DNAse hypersensitive site 4 (HS4) of the locus control region (LCR), a polymorphism of which is in linkage disequilibrium with the Xmn I site [28] , may affect direct or indirect interactions with the transcriptional repressor BCL11A [30] . This transcriptional repressor directly regulates HbF levels during the globin switch after birth [31] .…”

Section: Pharmacological Therapiesmentioning

confidence: 99%

Current and future alternative therapies for beta-thalassemia major

et al. 2016

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Beta-thalassemia is a group of frequent genetic disorders resulting in the synthesis of little or no β-globin chains. Novel approaches are being developed to correct the resulting α/β-globin chain imbalance, in an effort to move beyond the palliative management of this disease and the complications of its treatment (e.g. life-long red blood cell transfusion, iron chelation, splenectomy), which impose high costs on healthcare systems. Three approaches are envisaged: fetal globin gene reactivation by pharmacological compounds injected into patients throughout their lives, allogeneic hematopoietic stem cell transplantation (HSCT), and gene therapy. HSCT is currently the only treatment shown to provide an effective, definitive cure for β-thalassemia. However, this procedure remains risky and histocompatible donors are identified for only a small fraction of patients. New pharmacological compounds are being tested, but none has yet made it into common clinical practice for the treatment of beta-thalassemia major. Gene therapy is in the experimental phase. It is emerging as a powerful approach without the immunological complications of HSCT, but with other possible drawbacks. Rapid progress is being made in this field, and long-term efficacy and safety studies are underway.

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The modifying effect of Xmn1-HBG2 on thalassemic phenotype is associated with its linked elements in the beta globin locus control region, including the palindromic site at 5′HS4

Cited by 10 publications

References 24 publications

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Quantitative Age-specific Variability of Plasma Proteins in Healthy Neonates, Children and Adults

Molecular genetics of β-thalassemia

Current and future alternative therapies for beta-thalassemia major

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