Two New Large Deletions Resulting in εγδβ-Thalassemia

“…In addition, whenever indicated, specific studies such as tests for unstable Hbs, isoelectric focusing (IEF), structural characterization of the variant Hbs, and in vitro biosynthetic studies (15) were performed. Gene mapping analysis, dot-blot hybridization of polymerase chain reaction (PCR) amplified DNA with specific probes, and sequencing of the amplified DNA followed methodology described before (20)(21)(22)(23)(24). 4 …”

Section: Methodsmentioning

confidence: 99%

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Ефремов

2007

Hemoglobin

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This paper summarizes the results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the Republic of Macedonia. Over the past 40 years, population surveys of more than 22,000 participants (school children and workers) from all over the country, have shown that the average incidence of beta-thalassemia (thal) trait is 2.6%, ranging from less than 1% in the northeast to 10% in the south. The frequency of deltabeta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.3%. Screening of 9,619 newborns has shown that the frequency of alpha-thal trait is 1.5%, of which alpha-thal-2 is 1.45% and alpha-thal-1 is 0.05%. The molecular basis of the different forms of beta-thal and other hemoglobinopathies has been completely defined. Among the Macedonians, over 450 beta-thal chromosomes have been studied. Fifteen different beta-thal mutations have been detected, four of which [IVS-I-110 (G-->A), IVS-I-6 (T-->C), IVS-I-1 (G-->A), codon 39 (C-->T)] account for 85% of all beta-thal chromosomes. Among the Albanians, 48 beta-thal chromosomes have been studied. Eight different mutations have been detected, four of which [codon 39, -30 (T-->A), IVS-I-110, IVS-I-1] account for 85% of all beta-thal chromosomes. Four new mutations [-101 (C-->A), -87 (C-->G), -30, polyadenylation signal (poly A) (AATAAA-->AATGAA)] have been characterized. Molecular analyses of DNA from over 20 unrelated cases with deltabeta-thal have shown that this condition is caused by a 13 kb deletion (Sicilian type); in two families a deletion of 18 to 23 kb (Macedonian type of deltabeta-thal) was discovered. Molecular analyses of alpha-thal in the Republic of Macedonia have shown the following types of molecular defects: 20.5 kb deletion, 17.5 kb deletion, 3.7 kb deletion, poly A mutation (AATAAA-->AATGAA), and Hb Icaria [alpha142, Term-->Lys, TAA-->AAA (alpha2)]. The incidence of abnormal hemoglobins (Hbs) in the Republic of Macedonia is 0.4%. Three different alpha chain variants among 10 families, seven different beta chain variants among 33 families, two gamma chain variants in two newborns, one variant with an extended alpha chain, and Hb Lepore among 105 families, have been observed. Structural analysis of numerous cases with Hb Lepore showed that the variant was of the Washington-Boston type.

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“…The molecular defect (termed Anglo-Saxon deletion; Fig 3) was subsequently characterized as a deletion of nearly 96 kb that extended approximately 50 kb upstream of the e-gene and terminating in the second exon of the b-globin gene (Orkin et al, 1981). Since then, 11 different deletions causing ecdbthalassaemia (Fig 3) have been discovered (Van der Ploeg et al, 1980;Fearon et al, 1983;Pirastu et al, 1983;Curtin et al, 1985;Taramelli et al, 1986;Diaz-Chico et al, 1988;Driscoll et al, 1989;Trent et al, 1990;Fortina et al, 1991;Abels et al, 1996;Game et al, 2003;Harteveld et al, 2003). All, except for one deletion (Pirastu et al, 1983;Trent et al, 1990), are unique and several appear to be de novo.…”

Section: Family 3 (Deletion English Iv)mentioning

confidence: 99%

Heterogeneity of the ɛγδβ‐thalassaemias: characterization of three novel English deletions

et al. 2005

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Heterogeneity of the ecdb-thalassaemias: characterization of three novel English deletionsThe thalassaemias are inherited disorders classified genetically into a,b,c,db,d and ecdb varieties according to the type of globin(s) that are under-produced (Weatherall & Clegg, 2001). ecdb-thalassaemias are all caused by deletions of the b-globin gene cluster on chromosome 11p. At the molecular level, the deletions fall into two categories: group I removes all, or a greater part of the b-globin cluster, including the b-globin gene. Group II removes extensive upstream regions leaving the b-globin gene itself intact despite which, its expression is silenced because of inactivation of the upstream b-locus control region (b-LCR) (Grosveld et al, 1993). However, because of incomplete sequence data, the breakpoints of many of the early deletions have not been characterized. Recently, two novel deletions causing ecdb-thalassaemia have been reported; a 153 kb deletion removing the entire b-globin cluster (group I) in a Chilean family (Game et al, 2003), and an upstream deletion of 112 kb (group II) in a Dutch family (Dutch III) (Harteveld et al, 2003). The present study describes the characterization of three novel ecdb-thalassaemia deletions, in three English families, named English II, III and IV, to differentiate them from the previously reported English (I) deletion (Curtin et al, 1985).English II removes 98 kb extending from 8 kb upstream of the G c-globin gene, thus leaving the G c, A c and b-genes intact.English III and IV remove the entire b-globin cluster including several flanking olfactory receptor (HOR) genes. English IV removes more than 400 kb of this region of chromosome 11p and is the largest deletion reported so far. Although in later life, heterozygotes for ecdb-thalassaemia have a blood picture typical of b-thalassaemia trait but with normal A 2 levels, our

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Two New Large Deletions Resulting in εγδβ-Thalassemia

Cited by 21 publications

References 13 publications

A novel epsilon gamma delta beta thalassemia presenting with pregnancy complications and severe neonatal anemia

A novel epsilon gamma delta beta thalassemia presenting with pregnancy complications and severe neonatal anemia

Thalassemias and Other Hemoglobinopathies in the Republic of Macedonia

Heterogeneity of the ɛγδβ‐thalassaemias: characterization of three novel English deletions

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