MOLECULAR HETEROGENEITY OF HEREDITARY ELLIPTOCYTOSIS IN ITALY

Background. Common HE is the most prevalent clinical form of hereditar y elliptocytosis; its clinical findings vary considerably, ranging fro m an asymptomatic carrier state to a severe, even life-threatening hem olytic disorder. Structural modification and reduction of 4.1 protein, or abnormalities at the spectrin self-association site could lead to elliptocytes. Methods. Sixty-one Italian HE patients belonging to 28 f amilies were studied. Analysis of red blood cell cytoskeleton was perf ormed by means of SDS-PAGE, and spectrin dimer percentage was assessed by non denaturing polyacrylamide gel electrophoresis. Limited tryptic digestion of spectrin was employed in patients showing an abnormal di mer increase, and the amount of abnormal alpha I peptide was estimated . Molecular defects were detected by means of PCR of alpha and beta sp ectrin genes and direct sequencing of genomic DNA. Results. We found a very heterogeneous spectrum of cytoskeletal alterations: 18 (29%) sub jects showed partial protein 4.1 deficiency, whereas 31 (51%) displaye d an increased amount of spectrin dimers; we were not able to detect a ny alteration in 12 (20%) HE patients. Patients enrolled in this study were widely distributed throughout Italy. Conclusions. The subgroup o f HE patients related to 4.1 deficiency is homogeneously asymptomatic, whereas forms due to disruption of the spectrin tetramerization site are very heterogeneous, and clinical severity appears to be related to spectrin dimers and especially to spectrin content. These two paramet ers in turn are related to the presence of a low expression alpha alle le in trans and to the degree of disruption of head-to-head contact be tween alpha and beta chains.