Molecular characterization of beta-thalassemia intermedia in patients of
Italian descent and identification of three novel beta-thalassemia
mutations
S Murru, G Loudianos, M Deiana, C Camaschella, GV Sciarratta, S Agosti, MI Parodi, P Cerruti, A Cao and M Pirastu
Istituto di Clinica e Biologia dell'Eta Evolutiva, Universita degli Studi,
Cagliari, Italy.
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.
Volume 77,
Issue 6,
pp. 1342-1347,
03/15/1991
Copyright © 1991 by The American Society of Hematology
