Molecular genetics of hereditary elliptocytosis and hereditary spherocytosis.
Red cells ow their mechanical properties, that is, their resistance and their elastic deformability, to a protein network that laminates the lipid bilayer and to proteins spanning the latter. All proteins are interconnected. Their structure, as well as the structure of the corresponding genes, will be outlined. Numerous mutations have allowed to reclassify hereditary elliptocytosis (HE) and poikilocytosis (HP), and, more recently, hereditary spherocytosis (HS) into well defined subsets of hereditary hemolytic anemias. HE stems from changes in the SPTA1, SPTB, EL1 and (exceptionally) GPYC genes that encode spectrin alpha- and beta- chains, protein 4.1 and glycophorin C/D, respectively. HS derives from altercations in the ANK1, EPB3 and ELB42 genes, encoding ankyrin, band 3 and protein 4.2, respectively, and also in the SPTA1 and SPTB genes. We will present a repertory of the known mutations. Innumerable polymorphisms will not be considered here, except for a few remarkable ones. Some general points must be stressed on. (a) Clinically conspicuous disorders are often the result of two alleles interacting in trans to one another. Whereas one allele causes moderate symptoms by itself, the other one is usually silent in the simple heterozygous (and exceptionally in the homozygous) state. As a result, the number of potentially pathogenic alleles is much more important than had been initially suspected. (b) The reduction or the loss of a protein within multiprotein assemblies are frequently encountered in red cell membrane genetic diseases; it leads to the disruption of the complexes with the possible disappearance of the other proteins than the mutated protein. (c) The above genes being also expressed in nonerythroid tissues, one starts finding multisyndromic conditions adding non-hematological manifestations to hemolysis. It is puzzling, though, that such situations are not more frequent. (d) In practice, the molecular diagnosis of HE and HS has reached a semi-routine stage that helps very much the paediatricians and haematologists.