title: Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations.
abstract: In this study, we have defined by dot-blot analysis with allelic specific oligonucleotide probes or direct sequencing on amplified DNA the beta-thalassemia mutations in a large group of patients (23) of Italian descent with thalassemia intermedia. These patients had one parent with either the silent beta-thalassemia carrier phenotype or borderline-normal hemoglobin A2 (HbA2) levels (2.5% to 3.5%). Nearly all were genetic compounds for a severe beta-thalassemia mutation and a beta-thalassemia mutation associated with high residual output of beta-globin chains (beta + intervening sequence [IVS]-I-nt6, beta -87, beta -101), indicating that inheritance of a mild beta-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 beta + globin gene and found three novel beta-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 beta-globin gene (The reason for the presence of clinical manifestations in a beta-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 beta-globin gene sequences at the other locus.
authors.affiliation: Istituto di Clinica e Biologia dell'Età Evolutiva, Università degli Studi, Cagliari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Murru
authors.forename: G
authors.initials: G
authors.lastname: Loudianos
authors.forename: M
authors.initials: M
authors.lastname: Deiana
authors.forename: C
authors.initials: C
authors.lastname: Camaschella
authors.forename: G V
authors.initials: GV
authors.lastname: Sciarratta
authors.forename: S
authors.initials: S
authors.lastname: Agosti
authors.forename: M I
authors.initials: MI
authors.lastname: Parodi
authors.forename: P
authors.initials: P
authors.lastname: Cerruti
authors.forename: A
authors.initials: A
authors.lastname: Cao
authors.forename: M
authors.initials: M
authors.lastname: Pirastu
mesh_terms: D000328:Adult; D001345:Autoradiography; D001483:Base Sequence; D002872:Chromosome Deletion; D004247:DNA / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D005914:Globins / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007558:Italy / Q000453:epidemiology / Q000208:ethnology; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D015345:Oligonucleotide Probes; D010641:Phenotype; D013789:Thalassemia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology
chemical_list: D015345:Oligonucleotide Probes; D005914:Globins; D004247:DNA