Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations

S. Murru, G. Loudianos, M. Deiana, C. Camaschella, G. V. Sciarratta, S. Agosti, M. I. Parodi, P. Cerruti, A. Cao, M. Pirastu

Research output: Contribution to journalArticle

Abstract

In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the β-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent β-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe β-thalassemia mutation and a β-thalassemia mutation associated with high residual output of β-globin chains (β+ intervening sequence [IVS]-I-nt6, β-87, β-101), indicating that inheritance of a mild β-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the β+globin gene and found three novel β-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans β-globin gene (The reason for the presence of clinical manifestations in a β-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5 untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal β-globin gene sequences at the other locus.

Original languageEnglish
Pages (from-to)1342-1347
Number of pages6
JournalBlood
Volume77
Issue number6
Publication statusPublished - Mar 15 1991

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Thalassemia
Globins
beta-Thalassemia
Introns
Mutation
Genes
Substitution reactions
Hemoglobin A2
Oligonucleotide Probes
5' Untranslated Regions
Heterozygote
Nucleotides
Amino Acids
Molecules
DNA
Codon
Alleles
Phenotype

ASJC Scopus subject areas

  • Hematology

Cite this

Murru, S., Loudianos, G., Deiana, M., Camaschella, C., Sciarratta, G. V., Agosti, S., ... Pirastu, M. (1991). Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations. Blood, 77(6), 1342-1347.

Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations. / Murru, S.; Loudianos, G.; Deiana, M.; Camaschella, C.; Sciarratta, G. V.; Agosti, S.; Parodi, M. I.; Cerruti, P.; Cao, A.; Pirastu, M.

In: Blood, Vol. 77, No. 6, 15.03.1991, p. 1342-1347.

Research output: Contribution to journalArticle

Murru, S, Loudianos, G, Deiana, M, Camaschella, C, Sciarratta, GV, Agosti, S, Parodi, MI, Cerruti, P, Cao, A & Pirastu, M 1991, 'Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations', Blood, vol. 77, no. 6, pp. 1342-1347.
Murru S, Loudianos G, Deiana M, Camaschella C, Sciarratta GV, Agosti S et al. Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations. Blood. 1991 Mar 15;77(6):1342-1347.
Murru, S. ; Loudianos, G. ; Deiana, M. ; Camaschella, C. ; Sciarratta, G. V. ; Agosti, S. ; Parodi, M. I. ; Cerruti, P. ; Cao, A. ; Pirastu, M. / Molecular characterization of β-thalassemia intermedia in patients of Italian descent and identification of three novel β-thalassemia mutations. In: Blood. 1991 ; Vol. 77, No. 6. pp. 1342-1347.
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abstract = "In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the β-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent β-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5{\%} to 3.5{\%}). Nearly all were genetic compounds for a severe β-thalassemia mutation and a β-thalassemia mutation associated with high residual output of β-globin chains (β+ intervening sequence [IVS]-I-nt6, β-87, β-101), indicating that inheritance of a mild β-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the β+globin gene and found three novel β-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans β-globin gene (The reason for the presence of clinical manifestations in a β-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5 untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal β-globin gene sequences at the other locus.",
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N2 - In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the β-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent β-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe β-thalassemia mutation and a β-thalassemia mutation associated with high residual output of β-globin chains (β+ intervening sequence [IVS]-I-nt6, β-87, β-101), indicating that inheritance of a mild β-thalassemia allele, even in a single dose, is the most common molecular mechanism producing thalassemia intermedia in the Italian population. In three cases, in whom we failed to define by dot-blot analysis the mutations, we sequenced the β+globin gene and found three novel β-thalassemia mutations, which are certainly very rare because they have been hitherto detected solely in a single patient. These mutations consist of: (1) a T-A substitution at position 2 of IVS-I, in a patient compound heterozygote for this mutation and the -87 promoter mutation; (2) a G-C substitution at position 844 of IVS-II, in a patient heterozygous for this mutation who showed normal sequences at the in trans β-globin gene (The reason for the presence of clinical manifestations in a β-thalassemia heterozygote has not been defined.); and (3) a deletion of one nucleotide (-T) at codon 126, resulting in a frameshift and readthrough of the 5 untranslated region and most likely producing an elongated Hb molecule of 156 amino acid residues, in a patient heterozygous for this mutation with normal β-globin gene sequences at the other locus.

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