Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan.

Rund, Deborah; Cohen, Tirza; Filon, Dvora; Dowling, Carol E.; Warren, Tina C.; Barak, Igal; Rachmilewitz, Eliezer A.; Kazazian, Haig H.; Oppenheim, Ariella

doi:10.1073/pnas.88.1.310

Cited by 98 publications

(39 citation statements)

References 25 publications

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“…One of the mutations is an A --G transition in the last A of the hexanucleotide, AATAAA -* AATAAG, discovered in a patient of Kurdish Jewish extraction with transfusiondependent P-thalassemia major. This allele, which is linked to Mediterranean haplotype VII, was subsequently found to represent about 10% of thalassemia chromosomes in this ethnic group (22,23). However, homozygotes for the mutation have not yet been identified.…”

Section: Resultsmentioning

confidence: 99%

Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites.

Rund

Dowling

Najjar

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Two mutations in the (-globin poly(A) signal were identified in Israeli patients with 3+-tasmia by sequence analysis following PCR. One is a point mutation (AATAAA AATAAG) and the other is a 5-base-par deletion (AATAAA A ). The mutant genes were used to investigate the function of the poly(A) signal in vivo and to evaluate the mechanism whereby these mutations lead to a thalassemic phenotype. Analysis of RNA derived from peripheral blood demonstrated the presence ofelongated RNA species in patients carrying either mutation. Other aspects of RNA processing (initiation, splicing) were unimpaired. RNA obtained from the patients carrying the point mutation contained four discrete, extended RNA species, 1500-2900 nucleotides long, which were found to be polyadenylylated. Some normal cleavagepolyadenylylation was also observed. The 5-base-pair deletion completely abolished cleavage at the normal site. This deletion mutation resulted in a phenotype of (3+-thaassemia, thus providing evidence that the extended mRNAs are translatable in vivo. Furthermore, additional transcripts, >5 kilobases, presumably mRNA precursors, were found in all RNA samples, induding those of nonthalassemic controls. The extended transcripts of the poly(A) mutants, together with the high molecular weight precursors, suggest that the human -globin gene transcription unit is significantly longer than previously recognized.

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Section: Resultsmentioning

confidence: 99%

Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites.

Rund

Dowling

Najjar

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…DNA was isolated from peripheral blood and analysed as previously described [6]. Potymerase chain reaction, dot blotting and mutational analysis were performed as previously described [9]. The number of ~.-globin genes was determined using Southern analysis with BamHI digestion [7].…”

Section: Methodsmentioning

confidence: 99%

“…In some cases, a mutation, such as -101 C-T, has only minor consequences. This mutation was originally described in Turkey [2], and is also found in Italian and other Mediterranean populations [8,9]. In other cases, the molecular basis for silent carriership has not yet been identified [12].…”

Section: = Mean Corpuscular MCV Volumementioning

confidence: 98%

Silent carrier β-thalassaemia due to a severe β-globin mutation interacting with other genetic elements

et al. 1993

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Beta-thalassaemia is caused by the presence of two mutated beta-globin genes, one inherited from each parent. We describe two families in which the diagnosis of beta-thalassaemia intermedia was delayed because one of the parents, an obligatory heterozygote, had normal haematological parameters (silent carrier beta-thalassaemia). DNA analysis revealed that these silent carriers were heterozygous for a point mutation in the polyadenylation signal (AATAAA-AATAAG). This defect is known to cause a moderately severe beta-thalassaemia phenotype. In one case, concurrent deletional alpha-thalassaemia was found in the silent carrier, which may have contributed to the mild phenotype. The increasing availability of DNA analysis should allow prompt diagnosis of such cases. Silent carrier beta-thalassaemia presents a diagnostic challenge to the clinician who evaluates children with anaemia.

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“…Six different mutations in this element in the ß-globin gene have been described to date, but their occurence is uncommon. Two deletions (AATAAA/AAAA (14); AATAAA/A (15) and four point mutations (AATAAA/AACAAA (16); AATAAA/ AATGAA and AATAAA/AATAGA (11); AATAAA/ AATAAG (17) have been published to date. The mutation AATAAA/AATGAA was also described in a homozygous condition (18).…”

Section: Discussionmentioning

confidence: 99%

Clinical Expression of a Rare β-Globin Gene Mutation Co-Inherited with Haemoglobin E-Disease

Solinge¹,

Lind²,

Wijk³

et al. 1996

CCLM

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Summary:A single nucleotide substitution and the effect on the phenotype in an Indonesian family with ß-thalassaemia, HbE-trait and HbE-ß-thalassaemia is described. In the proposita (female, age 20 (Hb 7.4 mmol/1; MCV 72 fl; MCH 1.45 fmol; HbA 2 3.5%; HbF 2.4%)). an A/G mutation in the RNA cleavage and polyadenylation sequence was detected (AATAAA/AATAGA). Her sister (Hb 8.2 mmol/1; MCV 77 fl; MCH 1.60 fmol; HbA 2 /HbE 32.4%), carried a different mutation in the ß-globin gene (codon 25; G 129 /A), and consequently had HbE-trait. Their mother had a haemoglobin concentration of 6.4 mmol/1 (MCV 56 fl; MCH 1.20 fmol; HbA 2 /HbE 55.8%). She was compound heterozygous for the mutation in the poly -signal and HbE-trait. Using restriction enzyme analysis and linkage studies, we subsequently identified six family members with HbE-ß-thalassaemia, five with ß-thalassaemia and six with HbE-trait. Two individuals were unaffected. The mutation in the polyadenylation sequence causes a mild form of ß + -thalassaemia. The MCV and MCH in individuals with both ß-thalassaemia and HbE-trait were significantly lower, yet on average they were only slightly more anaemic than those carrying only the thalassaemic gene.

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Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan.

Abstract: ABSTRACTf-TThalassemia is a hereditary disease caused by any of 90 different point mutations in the (1-globin gene.

Cited by 98 publications

References 25 publications

Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites.

Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites.

Silent carrier β-thalassaemia due to a severe β-globin mutation interacting with other genetic elements

Clinical Expression of a Rare β-Globin Gene Mutation Co-Inherited with Haemoglobin E-Disease

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