A novel molecular basis for β thalassemia intermedia poses new questions about its pathophysiology

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 3251-3255 ◽  
Author(s):  
Anuja Premawardhena ◽  
Christopher A. Fisher ◽  
Nancy F. Olivieri ◽  
Shanthimala de Silva ◽  
Jackie Sloane-Stanley ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Genetic Factors ◽  
Globin Gene ◽  
Gene Arrangement ◽  
Gene Interactions ◽  
Sri Lankan ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Early Management ◽  
Consistent Finding

AbstractDuring a study of the molecular basis for severe forms of β thalassemia in Sri Lanka, 2 patients were found to be heterozygous for β thalassemia mutations. Further analysis revealed that one of them has a previously unreported molecular basis for severe thalassemia intermedia, homozygosity for quadruplicated α globin genes in combination with heterozygous β thalassemia. The other is homozygous for a triplicated α globin gene arrangement and heterozygous for β thalassemia. Their differences in clinical phenotype are explainable by the interaction of other genetic factors and, in particular, their early management. The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with β thalassemia intermedia associated with extended α globin gene arrangements. The hemoglobin (Hb) F levels in these patients with severe β thalassemia intermedia, compared with other forms of this condition in the Sri Lankan population and elsewhere, are unusually low, a consistent finding in extended α globin gene interactions and in dominant β thalassemia, raising the possibility that increased levels of HbF production in β thalassemia may require mutations at both β globin gene loci.

scholarly journals Beta zero-thalassemia in association with a gamma-globin gene quadruplication

Blood ◽  
1986 ◽  
Vol 68 (6) ◽  
pp. 1394-1397
Author(s):  
KG Yang ◽  
JZ Liu ◽  
F Kutlar ◽  
A Kutlar ◽  
C Altay ◽  
...  
Keyword(s):  
Clinical Condition ◽  
Globin Gene ◽  
Normal Chromosome ◽  
Gene Arrangement ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Gamma Globin ◽  
Alpha Globin

We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma- globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.

scholarly journals Beta zero-thalassemia in association with a gamma-globin gene quadruplication

Blood ◽  
1986 ◽  
Vol 68 (6) ◽  
pp. 1394-1397 ◽  
Author(s):  
KG Yang ◽  
JZ Liu ◽  
F Kutlar ◽  
A Kutlar ◽  
C Altay ◽  
...  
Keyword(s):  
Clinical Condition ◽  
Globin Gene ◽  
Normal Chromosome ◽  
Gene Arrangement ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Gamma Globin ◽  
Alpha Globin

Abstract We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma- globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.

Differences in Fetal Hemoglobin Induction in Sickle Cell Disease and beta-Thalassemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 555-555 ◽  
Author(s):  
Hassana Fathallah ◽  
Ali Taher ◽  
Ali Bazarbachi ◽  
George F. Atweh
Keyword(s):  
Gene Expression ◽  
Sickle Cell Disease ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Mrna Levels ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Cell Disease ◽  
Globin Mrna ◽  
Globin Gene Expression

Abstract A number of therapeutic agents including hydroxyurea, butyrate and decitabine have shown considerable promise in the treatment of sickle cell disease (SCD). However, the same agents have shown less clinical activity in β-thalassemia. As a first step towards understanding the molecular basis of the different clinical responses to these agents, we have studied the mechanisms of induction of fetal hemoglobin (HbF) by butyrate in BFU-E derived cells from 5 patients with SCD and 9 patients with β-thalassemia intermedia. Exposure to butyrate resulted in a dose-dependent augmentation of γ-globin mRNA levels in erythroid cells from patients with SCD. In contrast, induction of γ-globin expression in erythroid cells from patients with β-thalassemia intermedia was only seen at a high concentration of butyrate. The increase in γ-globin mRNA levels in patients with SCD and β-thalassemia intermedia was associated with opening of the DNA structure as manifested by decreased DNA methylation at the γ-globin promoters. Interestingly, butyrate exposure had markedly different effects on the expression of the β- and α-globin genes in the two categories of patients. Butyrate decreased the level of β-globin mRNA in 4 out of 5 patients with SCD (P = 0.04), while in β-thalassemia the levels of β-globin mRNA did not change in 7 patients and decreased in 2 patients after butyrate exposure (P = 0.12). Thus in patients with SCD, the effects of the induction of the γ-globin gene on the γ/(β+γ) mRNA ratios were further enhanced by the butyrate-mediated decreased expression of the β-globin gene. As a result, γ/(β+γ) mRNA ratios increased in all patients with SCD, with a mean increase of 31% (P = 0.002). In contrast, butyrate increased γ/(β+γ) mRNA ratios only in 4 out of 9 patients with β-thalassemia, with a more modest mean increase of 12% (P = 0.004). Interestingly, the decreased β-globin expression in patients with SCD was associated with closing of the DNA configuration as manifested by hypermethylation of DNA at the promoter of the β-globin gene while methylation of the same promoter did not change following butyrate exposure in patients with β-thalassemia intermedia. More surprisingly, the expression of the α-globin genes increased following butyrate exposure in 4 out of 9 patients with β-thalassemia, while the levels of α-globin mRNA decreased in 4 out of 5 patients with SCD. As a result, the favorable effects of the butyrate-induced increase in γ-globin gene expression on the α: non-α mRNA imbalance in patients with β-thalassemia intermedia were partly neutralized by the corresponding increase in α-globin gene expression. These differences may explain, at least in part, the more favorable effects of inducers of HbF in SCD than in β-thalassemia. Further studies are necessary to fully understand the molecular bases of the different responses to agents that induce HbF in patients with these disorders.

A Deletion Of About 11kb Starting From 0.5 Kb 5’ To The β-Globin Gene Reactivates Foetal Haemoglobin and Leads To β Thalassemia Intermedia When Associated To a β-Zero Thalassemic Mutation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4702-4702
Author(s):  
Photis Beris ◽  
Tanguy Araud ◽  
Lorella Clerici ◽  
Anne-Pascale Grandjean ◽  
Georgios Georgiou ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Globin Genes ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Chromosome 11 ◽  
Exact Size ◽  
Hg19 Assembly

Background and Aims Thalassemia intermedia is characterized by severe but not transfusion dependent anemia secondary to seriously decreased production of hemoglobin (Hb). In the majority of cases, thalassemia intermedia concerns β-globin gene pathology. The molecular basis of thalassemia intermedia is heterogeneous. Here we describe a case of an adopted child native of Myanmar suffering from β-thalassemia intermedia which was proved to be secondary to a β-zero thalassemia associated with a not yet described deletional form of HPFH. Patient, Material and Methods Male child born in 1994 with Hb varying between 50 and 60 g/l, with Hb A2 of 2.1% and Hb F of 97.9%. No α-thalassemia or α-gene triplication was found. Sequencing of β-globin gene put in evidence the IVS-I-1 (G>T) or c.92+1G>T mutation in a “homozygous” state. This mutation is known to produce a β-zero thalassemia. The patient was treated with hydroxyurea as well as with erythropoietin and the Hb value was improved up to 86 g/l with normal leucocytes and platelets count. No transfusion was given during this period of treatment. Because the clinical phenotype was not typical for β-thalassemia major homozygous for the above mentioned mutation, we analyzed β-globin cluster looking for the presence of a possible deletion responsible for Hb F activation. Patient’s DNA was extracted with commercial columns from peripheral blood cells. Analysis of deletion in the beta cluster was performed by MLPA (Multiplex Ligation Probe Analysis) MRC-Holland P-102 probe mix. The data obtained were analyzed with the Coffyanalyzer software. The exact size of the deletion was determined by PCR with the primers: DelHBB_F: 5’-AGGCTTGGCTCCTGTTTAGT-3’, DelHBB_R: 5’-TGAGAG CTGCTGAGTTGTGT-3’ Results A heterozygous deletion in the beta-globin cluster has been detected by MLPA. This deletion was located between the coordinated 5,237,089 and 5,251,133 on chromosome 11 - (GRCh37/hg19 Assembly). The deletion starts about 0.5 kb 5’ upstream the HBB gene, between HBB and HBD genes, and ends about 9 kb downstream the 3’ end of HBB gene. The density of the MLPA probes is not sufficient to determinate the exact size of the deletion (between 14.3kb and 9.6 kb). A PCR using the primers DelHBB_F and DelHBB_R determined the size of this deletion to around 11kb. Conclusions Our molecular biology studies confirmed our clinical suspicion of association of HPFH with β-zero thalassemia. In fact, we put in evidence a not yet described (to our knowledge) 11kb deletion, which is very similar to the 12.6kb deletion of the Dutch β-zero thalassemia (Br J Haematol 67:369;1987) and to the Asian Indian 10.3kb deletion described by Craig et al (Br J Haematol 82:735;1992). Our deletion starts between δ and β-globin gene, almost 0.5 kb upstream of the β-gene, and goes about 9 kb downstream of 3’ end of the β-gene. The exact borders of the deletion are currently under investigation by PCR and appropriate primers. The pathophysiology of reactivation of γ-globin genes in our case is not yet known. We raise the following hypothesis: does this deletion bring an enhancer located 3’ to β-globin gene, close enough to the γ-genes, so that transcription of these genes continues after birth? In vitro studies in expression systems (constructs) are currently performed to elucidate the exact mechanism of γ-globin activation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals β-Intermediate Thalasemia: triplication of genes α / β thalassemia heterozygous in Spain

ANALES RANM ◽  
2021 ◽  
Vol 138 (138(01)) ◽  
pp. 60-71
Author(s):  
Paloma Ropero ◽  
Fernando Ataulfo González Fernández ◽  
Jorge Martínez Nieto ◽  
Williana Melissa Torres Jiménez ◽  
Celina Benavente Cuesta
Keyword(s):  
Hematological Parameters ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Transfusion Therapy ◽  
Group Iii ◽  
Group I ◽  
Caucasian Origin ◽  
Group Ii

Objectives. Check with hematological data that the diagnosis and clinical grade of β-thalassemia intermedia can be established when a triplication of genes alpha (αααanti 3.7) and heterozygous β-thalassemia are coherent. Methods. Retrospective study in which 73 patients of Caucasian origin participated, who simultaneously showed a tripling or quadrupling of the genes α and heterozygous β-thalassemia. Screening for the most frequent α-thalassemia mutations, as well as gene triplication (αααanti 3.7) was carried out by multiplex PCR followed by reverse hybridization and confirmed by MLPA. The molecular diagnosis of β-thalassemia was carried out by automatic sequencing according to the Sanger’s method. Results. Genotypes have been classified into three groups according to the number of α-globin genes and the severity of the alteration in the β-globin gene. All had a mutation in the β-globin gene (β0-thalassemia, severe β+-thalassemia, and mild β+-thalassemia). Group I patients who have inherited 6 α globin genes. Group II and group III have inherited 5 α globin genes. In group III, the patients were carriers of mutations affecting the β and δ globin genes. The most significant hematological parameters were hemoglobin levels, mean corpuscular volume, red deep width, and percentage of fetal hemoglobin. Conclusions. In group I, patients who have inherited of 6 α globin genes, either by homozygous triplication (ααα/ααα) or heterozygous quadruplication (αααα/αα), with heterozygous β-thalassemia results in severe to moderate anemia that may require transfusion therapy, being the severity of the β-globin gene mutation that would determine the clinical variation. Group II patients behaved phenotypically like mild thalassemia intermedia. Finally, group III patients behaved like a thalassemic trait since all were carriers of mutations that increase the overexpression of g genes.

Genetic Analysis of Candidate Modifier Polymorphisms in β-Thalassemia/Hb E Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3781-3781
Author(s):  
Suthat Fucharoen ◽  
Pranee Winichagoon ◽  
Orapan Sripichai ◽  
Thongperm Munkongdee ◽  
Chutima Kumkhaek ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Clinical Symptoms ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Globin Genes ◽  
Nucleotide Polymorphisms ◽  
Relative Contribution ◽  
Modifying Factors ◽  
Hb E ◽  
Genes Encoding

Abstract β-Thalassemia/Hb E patients encompass a number of clinical severities, ranging from nearly asymptomatic to transfusion-dependent thalassemia major. This has been well documented, but the causes of the variability and the molecular basis of the interaction remain unexplained. In general any factor capable of reducing the degree of alpha-globin-beta-globin chain imbalance will result in a milder form of thalassemia. The major modifying factors demonstrated in the mild cases are coinheritance of mild β+-thalassemia and Hb E genes, coinheritance of α-thalassemia and increased production of Hb F. However, the fact that many patients who have seemingly identical genotypes, β0-thalassemia/Hb E, and do not have a detectable α-thalassemia or increased Hb F production still have mild clinical symptoms, while other patients have a very severe clinical condition similar to homozygous β0-thalassemia. This variation suggests that other unknown modifying genetic factors may contribute to severity of the disease. To assess the relative contribution of genetic factors in the variation of severity among β-thalassemia/Hb E patients, we conducted a prospective study searching for modifying factors in almost 1100 Thai/Chinese β0-thalassemia/Hb E patients from Thailand using an automated, chip-based platform based on mass spectrometry (Sequenom’s MassARRAYTM system). A map of ~80 single nucleotide polymorphisms (SNPs) has been constructed spanning more than 80 kb, including the locus control region (LCR) and all beta-like globin genes. These SNPs were identified through resequencing and from the public domain, including well-characterized restriction fragment length polymorphisms (RFLPs) used in prior haplotype studies. Included in this panel are assays for polymorphic sites reported to influence globin gene expression, specifically Gγ-Xmn I polymorphism and BP-1 binding site upstream of β-globin gene. Genotyping of other candidate modifier loci, including SNPs in genes encoding alpha hemoglobin stabilizing protein (AHSP), β-globin gene repressor BP-1 protein, erythropoietin (Epo), and transcription factors; GATA-1, EKLF, NF-E2, has been studied. To identify additional modifier loci, carefully selected patient sub-groups representing the extremes in disease severity either mild or severe have been selected for DNA pool construction to be used in a genomewide screen involving up to 100,000 validated gene-based SNPs. It is expected that this genomewide screen will yield important information on the role of candidate genes and may uncover the association of novel polymorphisms with severity heterogeneity in β-thalassemia/Hb E disease.

scholarly journals EFFECT OF CIS ACTING POTENTIAL REGULATORS IN THE ß GLOBIN GENE CLUSTER ON THE PRODUCTION OF HBF IN THALASSEMIA PATIENTS

2013 ◽  
Vol 5 (1) ◽  
pp. e2013012 ◽  
Author(s):  
Anita Nadkarni
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Cis Acting ◽  
Indian Origin ◽  
In Trans ◽  
Severity Of The Disease ◽  
In Cis

The clinical presentation of   b-thalassemia intermedia phenotypes are influenced by many factors .The persistence of fetal hemoglobin and  several polymorphisms located in the promoters of  g- and b-globin genes are some of them .The aim of this study was to evaluate the combined effect of  the -158Gg (CàT) polymorphism and of the (AT)x(T)y configuration, as well as their eventual association with elevated levels of HbF  in  b-thalassemia carriers, b-thalassemia Intermedia , b-thalassemia major and normal controls of Indian origin. The -158 Gg T allele was found to be associated with increased levels of HbF in b-thalassemia carriers, and not in wild-type subjects. In the homozygous group the -158 Gg T allele was significantly higher in the thalassemia intermedia group (66%) as against the thalassemia major group (21%). The (AT)9(T)5 allele did not show any association with raised HbF levels. However 24% of milder cases showed presence of this allele. This study suggests that two regions of the b globin cluster, whether in cis or in trans to each other, can interact to enhance HbF expression when a b thalassemic determinant is present in heterozigosity and help in amelioration of the severity of the disease in homozygotes.

scholarly journals Alpha hemoglobinophaties in Rosario, Argentina

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Mara Jorgelina Ojeda ◽  
Susana Mabel Perez ◽  
Arianna Flavia Pratti ◽  
Karina Lucrecia Calvo ◽  
Mariana Paula Raviola ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Sickle Cell Trait ◽  
Clinical Phenotype ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Structural Alterations ◽  
Alpha Thalassemia ◽  
Molecular Studies ◽  
Alpha Globin ◽  
Hb H Disease

<p>Hemoglobinopathies are the most common recessive diseases worldwide. While the molecular basis of <span>β</span>-thalassemia in Rosario has been addressed, that of α-thalassemia and α structural alterations, has not. In this study 105 individuals from different families referred to our center were investigated for alpha hemoglobinopathies because of low MCV (15%. Six of them with a clinical phenotype of thalassemia intermedia were diagnosed as Hb H disease (five cases) and Hb H like (one case). It also included one patient with sickle cell trait, confirmed by hematological and molecular studies. We were able to identify alpha globin genes mutations in 92 individuals (87.6%): 88 patients with alpha thalassemia, 3 patients with structural alterations and one with both. In total, 13 individuals (12.4%) had no identified α-globin mutation. This study is the first to deal with the molecular basis of α-hemoglobinophaties in Rosario.</p><p> </p><p>血红蛋白病是全世界最常见的隐性疾病。 尽管我们已对罗萨里奥β地中海贫血的分子基础作出阐述，但是α地中海贫血和α结构性变化的分子基础尚未得到阐明。 在本研究中，105例来自不同家庭转诊至我中心的个体因MCV低(15%而接受了α血红蛋白病调查。 他们中具有中间型地中海贫血临床表型的六例被诊断为Hb H病（五例）和Hb H样（一例）。 其中还包括一例通过血液学和分子研究证实具有镰状细胞特征的患者 。 我们能够在92例个体(87.6%)中识别出α珠蛋白基因突变：88例有α地中海贫血 ，3例有结构性变化，还有一例两者均有。 总计13例个体(12.4%)未被识别出有α珠蛋白突变。 本研究是第一项针对罗萨里奥α地中海贫血分子基础的研究。</p>

Identification of a Transcription Factor Potentially Involved in γ-Globin Gene Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2701-2701
Author(s):  
Michela Grosso ◽  
Giovanni Amendola ◽  
Raffaella Petruzzelli ◽  
Stella Puzone ◽  
Raffaele Sessa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Cluster ◽  
Therapeutic Potential ◽  
Globin Gene ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Severe Condition ◽  
Transfusion Therapy ◽  
Globin Gene Cluster ◽  
Globin Gene Expression

Abstract The switch from fetal to adult globin gene expression occurs around birth when fetal hemoglobin (HbF) production gradually declines within a few months. Much effort is underway to clarify the molecular basis of this mechanism, since impaired hemoglobin switching leading to persistent expression of fetal globin genes in adults (HPFH) offers therapeutic potential for hemoglobinopathies (S.L. Thein. Br. J. Haematol2004; 124: 264–74). In order to identify and study regulatory factors putatively involved in γ-globin gene expression, we examined the reticulocyte mRNAs differently expressed in three siblings (one brother, 54 years-old and two sisters 35- and 37-years old, respectively). The eldest brother had been referred to Umberto I Hospital for evaluation of a severe condition of β-thalassemia intermedia on chronic transfusion therapy since 1990. Both of his sisters resulted clinically affected by a milder form of thalassemia intermedia, non-transfusion dependent, showing Hb values around 8.4 g/dL, Hb A2 levels from 6.0 to 7.9% and HbF ranging from 14.5 to 27.6%, values higher than those resulted in their brother (5.9% Hb A2 and 7.2% HbF). Molecular analysis was performed on DNA extracted from peripheral leucocytes and revealed the same β-globin gene cluster genotype for all these subjects who resulted homozygous for the β+ IVSI-6 (C→T) mutation associated to haplotype VI chromosomes. Different levels of HbF were thus presumably responsible of different clinical phenotypes. To investigate the possible causes of the variations in γ-globin gene expression, extensive sequence analysis was performed on putative regulatory regions within the β-globin gene cluster (Zhi-Hong Lu et al., Blood1996; 87: 1604–11). Results showed the same genetic background in all the siblings. It was thus supposed that genetic determinants external to the β-globin gene cluster were responsible of the different γ-globin gene expression. To explore this hypothesis, the reticulocyte transcriptome was analyzed by a differential mRNA display approach. Reticulocytes were isolated from peripheral blood and total RNA extracted for all family members. Our study revealed several bands differentially displayed in the sample from the more severely affected sibling respect to his sisters. Selected bands were cloned in a pGEM T-vector (Promega, WI) and sequenced. Comparative sequence searches were performed using the BLAST algorithm. Preliminary data gave, for two of the clones originated from bands with increased expression in the brother, a complete homology (greater than 95%) with the cDNA sequence of a cold shock domain protein, displaying features of a repressor factor for several hematopoietic genes (Horwitz M. et al. JBC1994; 269: 14130–39; P. Coles et al. Nucleic Acids Res1996; 12: 2311–17).

Severe Thalassemia Intermedia Resulting From Coinheritance of IVSI-110 G>A Beta Gene Mutation and Duplication of Alpha-Globin Gene Cluster in Homozygosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2011-2011 ◽  
Author(s):  
Chiara Refaldi ◽  
Wilma Barcellini ◽  
Elena Cassinerio ◽  
Giovanna Graziadei ◽  
Maria Domenica Cappellini
Keyword(s):  
Gene Cluster ◽  
Molecular Mechanisms ◽  
Globin Gene ◽  
Clinical Severity ◽  
Globin Genes ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Globin Gene Cluster ◽  
Increased Risk ◽  
Alpha Globin

Abstract Abstract 2011 Poster Board I-1033 Introduction The clinical severity of thalassemia intermedia depends on the degree of a/non-a-chains iimbalance. Among the molecular mechanisms responsible for thalassemia intermedia is the coinheritance of excessive a-globin gene production with a defective beta-globin gene. Materials and Methods: we describe an Italian family where thalassemia intermedia apparently segregates as a dominant form but it tourned out to be due to the coinheritance of a beta-globin mutation and a duplication of the alpha-globin gene cluster. The father (aged 51yrs) showed a well tolerated severe chronic hemolytic anemia (Hb 7.5-8.5 g/dL) not transfusion dependent, jaundice, splenomegaly and leg ulcers:The mother (aged 46yrs) has a completely normal hematological and hemoglobin pattern. Two sons (19 and 14 yrs) showed more severe clinical manifestations than the father. They underwent splenectomy at 12 and 13 years respectively without any benefit and afterwards they become transfusion dependent. Results: The hemoglobin analysis revealed that the father and the sons were heterozygotes for the beta mutation IVSI-110 G>A. MLPA analysis of the alpha-globin gene cluster disclosed a full duplication of the alpha-globin locus, spanning a 175 kb from the telomere to the 3'HVR downstream of the alpha-globin gene and including the upstream regulatory element HS-40. This rearrangement increases the number of the active alpha-globin genes in cis from 2 to 4.Surprisengly it was found in heterozygosis in both parents and in homozygosis in both sons. The hematological and molecular data of the family are reported in the table. In the father the 6 alpha-globin genes led to increased synthesis of alpha-chains; the coinheritance with a beta-thalassemia mutation causes a moderate/severe thalassemia intermedia phenotype. The presence of 8 alpha-globin genes in the sons raises further the degree of globin-chains imbalance and exacerbates the clinical phenotype. It is important to note that splenectomy worsened the clinical course.in the 2 homozygotes for the alpha duplication. Conclusions: Based also on previous experience we suggest that splenectomy in patients with a real excess of alphaa chain production is unconvenient since a large amount of circulating red cells with precipitated alpha chains may be responsible for increased hemolysis as well as increased risk of thrombosis This family moreover raises concerns regarding genetic counselling, suggesting that whenever one of the partner is affected by TI it is advisable a complete molecular screening of the couple in order to exclude any possible alpha gene defects interaction Disclosures: No relevant conflicts of interest to declare.

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