Genotyping and phenotyping characteristics in hereditary red cell membrane disorders

Red cell membrane proteins are composed of cytoskeletal proteins (spectrins, actin, and protein 4.1), integral proteins (band 3, and glycophorins), and anchoring proteins (ankyrin and protein 4.2). In disease states, abnormalities of α-spectrin, β-spectrin and protein 4.1 are now known as pathognomonic for hereditary elliptocytosis. The positions affected in these membrane protein genes were well correlated with the severity of the clinical findings and of the anomalies of their membrane ultrastructure and functions, as shown at best in three independent traits of β-spectrin anomalies; β-spectrin Lel'uy, β-spectrin Tokyo, and β-spectrin Nagoya. It should also be noted that the gene mutations of the C-terminal region of α-spectrin was strictly associated with hereditary elliptocytosis, contrary to the gene mutations all other regions, especially at the N-terminal region of α-spectrin which were associated with hereditary pherocytosis. In hereditary spherocytosis, which is most common in red cell membrane disorders, the gene mutations of ankyrin, band 3, and protein 4.2 were predominant. This disorder was found nearly exclusively in heterozygous states, rarely in homozygous states. It is also important to note that the incidence of the gene mutations pathognomonic for this disorder demonstrated great differences among various ethnic groups. The phenotypic characteristics of red cell membrane structure examined by electron microscopy demonstrated that total deficiency of band 3 proteins due to a homozygous nonsense mutation of the band 3 gene showed extremely unstable membrane ultrastructure, contrary to the total deficiency of protein 4.2 due to homozygous missense mutations with a moderate instability of the cytoskeletal network and the integral protein. Even in total deficiencies of protein 4.2, the phenotypic expressions were variable. Genotypic and phenotypic expressions in red cell membrane disorders are reviewed as based on the results from our laboratory for the recent 25 years.