Turi Lombardo

Molecular basis of α-thalassemia in Sicily

Abstract To evaluate the allelic frequency and genetic diversity of α-thalassemia defects in Sicily, both epidemiological and patient-oriented studies were carried out. For the epidemiological study, phenotypic data were collected on more than 1000 Sicilian individuals. Among them, 427 were explored at the molecular level for nine α-thalassemic variants known to be common in the Mediterranean region. Our data reveal an allele frequency of 4.1% for α+-thalassemia matching that of β-thalassemia in this region. The presence of α°-thalassemia (––MEDI and ––CAL) was observed only in the group of referred patients. Newly acquired nucleotide sequence data on the deletional breakpoint of ––CAL allowed us to design a simple PCR-based procedure for exploring this allele. The data also provide additional information concerning the genetic mechanisms involved in such large deletions.

Multiple molecular bases for thalassemia intermedia in east Sicily.

The existence of forms of P-thalassemia with intermediate severity has been long known, and the name thalassemia intermedia is used to describe a widespread spectrum of patients. The criteria used were both clinical and hematological or, frequently, based on moderate transfusional needs. Nevertheless, characterization of molecular defect(s) in these cases has been only sporadic, made in individual cases or in short, ethnically homogeneous series. The principles of such characterizations are based on the knowledge that the factor determining the severity of the disease is the degree of globin chain imbalance, due to the deleterious effect of excess unpaired a chains on erythroid cells.’ In theory at least, it is clear that there are three ways of reducing this effect: a reduction in a-chain production, the intrinsically mild nature of the &gene defect, or an unusually high production of y-chains able to combine with the excess a-chains. Examples have been given of all of these three mechanisms. In short, local series, there was apparently a predominance of a single pathophysiology.’ ’

Annotated Definition of BCL11A and HMIP-2 Haplotypes Through the Analysis of Sicilian β-Thalassemia Patients with High Levels of Fetal Hemoglobin

Fetal hemoglobin (Hb F) is the principal ameliorating factor of β-thalassemia (β-thal) and sickle cell disease. Persistent production in adult life is a quantitative trait regulated by loci inside or outside the β-globin gene cluster. From genome-wide association studies, principal quantitative trait loci (QTL) (accounting for 50.0% of Hb F variability in different populations) have been identified in the BCL11A gene, HBS1L-MYB intergenic polymorphism and the β-globin gene cluster itself. In this study, we analyzed quantitative trait haplotypes in two Sicilian families with extremely mild β-thal and unusually high Hb F expression, in order to examine possible genetic background variations in a similar β-thalassemic phenotype. This study redefines the linkage disequilibrium blocks at these loci, but also shows slight differences between probands in haplotype combinations which could reflect different mechanisms of high Hb F production in patients with β-thal. We proposed a haplotype-based approach as a useful tool for the understanding of β-thal phenotype variation in patients with similar β-thalassemic backgrounds in an attempt to answer the recurring question of why patients with the same β-thalassemic genotype show different phenotypes.