Hereditary Red Cell Membrane Disorders in Japan: Their Genotypic and Phenotypic Features in 1014 Cases Studied

This study describes the characteristic features of the incidence of hereditary red cell membrane disorders in the Japanese population based on studies of 1014 cases of these disorders from 605 kindred. Among them, there were 581 cases of hereditary spherocytosis (HS) from 303 kindred, 137 cases of hereditary elliptocytosis (HE) from 68 kindred, 104 cases of hereditary stomatocytosis (HSt) from 64 kindred, and 34 cases of protein 4.2 (P4.2) anomalies from 20 kindred, and 41 cases of membrane lipid anomalies from 27 kindred. In HS patients, eleven mutations of the band 3 (B3) gene, 15 mutations of the ankyrin gene, and three mutations of the protein 4.2 (P4.2) gene, which are pathognomonic for this disorder, were identified. Most of these mutations had not been reported and, with few exceptions, were specific to the Japanese population. P4.2 abnormalities also appear to be unique to the Japanese population. The biochemical and biophysical functions of P4.2 are associated with stabilization of the cytoskeletal network by anchoring it to integral proteins (especially B3). Biochemical and genetic analyses of the HE patients revealed one family with an α-spectrin (Sp) anomaly (HE [α(1/74)]) and three kindred with β-spectrin abnormalities (β-Sp Yamagata, β-Sp Tokyo, and β-Sp Nagoya) due to abnormal splicings of the β-Sp gene. On the basis of these observations, the relationship between the genotypes and phenotypes is reviewed. In addition, the morphogenesis of red cell membranes with regard to the sequential expression of these membrane proteins was also discussed. Finally, from the standpoint of gene expression, a possible role of gene methylation as an epigenetic control was proposed.