MOLECULAR GENETICS OF LEAKY RED CELL (LRC) SYNDROMES

In many common genetic diseases, the responsible genes have been identified and studied in great detail. This allowed improved diagnostic procedures, notably in the prenatal period, and helped take steps towards specific treatments. The vast majority of genetic disorders, however, are rare and frequently misdiagnosed. The objective of this project is to elucidatethe genomic bases and to facilitate the diagnosis and rationalise the treatment of the leaky red cell syndromes (LRC). These diseases include the hereditary stomatocytosis and allied disorders which are characterized by an abnormal permeability of the red cell membrane to univalent cations Na and K. Stomatocytes are red blood cells having a slit-like central zone of pallor on dried smears. This shape abnormality appears related to the intracellular concentration of monovalent cations that is critical for the maintenance of erythrocyte deformability. A net increase in Na and K causes water enter, forming stomatocytes or hydrocytes, whereas a net loss of monovalent cations produces dehydrated red cells or xerocytes. These disorders are inherited as an autosomal dominant pattern and are more heterogeneous than previously thought. For example dehydrated hereditary stomatocytosis includes kindreds showing pseudohyperkalemia or perinatal edema, or both; the overhydrated hereditary stomatocytosis remainds elusive despite the manifest lack of the enigmatic protein stomatin in the erythrocyte membrane. In all cases were splenectomy has been performed, this procedure has conferred a marked risck for thrombosis in adult life. The aims of our project are: 1) identification of the responsible genes and proteins of LCR sindromes; 2) understanding of the pathophysiology at the cellular and molecular level; 3) improving in diagnosis and treatment.