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

Abstract

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.

Clinical and genetic diagnosis of thirteen Japanese patients with hereditary spherocytosis

“…Previously, EPB42 (SPH5) was considered the most common subtype. However, the distribution of HS-related variants observed in this study was different from that identified in a previous study on Japanese patients with HS 15 , 16 . The reason for this difference is unknown; however, the total number of samples examined in the present study is too small to be compared with this previous study.…”

“…Inoue et al analyzed the genetic backgrounds of Japanese HS patients using sodium dodecyl sulfate–polyacrylamide gel electrophoresis and reported band 3 deficiency (SPH4) in 32% of the patients, spectrin deficiency (corresponding to SPH2 and SPH3) in 15%, protein 4.2 deficiency (SPH5) in 6%, ankyrin deficiency (SPH1) in 2%, combined deficiency in 36%, and no abnormality in 9% 14 . In contrast, Yawata et al analyzed 60 Japanese patients with HS using a similar method and detected protein 4.2 deficiency (SPH5) in 45% of the patients, band 3 deficiency (SPH4) in 20%, and ankyrin deficiency (SPH1) in 7%, while 28% of the patients had an unknown etiology 15 , 16 . Genetic variants in ANK1 were analyzed by Nakanishi et al 12 , who identified 16 variants in 49 patients with HS, suggesting that ANK1 variants (SPH1) are not rare in the Japanese population.…”

Analysis of erythrocyte membrane proteins in patients with hereditary spherocytosis and other types of haemolytic anaemia

“…Ankyrin abnormalities have been reported in Western countries. However, in Japan, HS cases with ankyrin abnormalities are rare owing to a small percentage and had severe anaemia [2]. Although the abnormality may be identified using SDS-PAGE, detection is challenging because the ankyrin protein, despite its large molecular weight, exhibits a thin band image directly under spectrin; therefore, qualitative abnormality genetic testing may be required for diagnosis [11].…”

“…In patients with HS, the erythrocyte membrane glycoproteins spectrin, ankyrin, band 3 protein, and band 4.2 are defective, as shown by biochemical analysis [1]. The ratio of band 3 protein was found to decrease from 20% to 30% in patients with HS [2]. Of note, patients with HS without a decrease in band 3 protein have quality dysfunction [3].…”

A large family of hereditary spherocytosis and a rare case of hereditary elliptocytosis with a novel SPTA1 mutation underdiagnosed in Taiwan: A case report and literature review

“…[ 27 ] In Japan, HE accounts for 13.5% of hereditary red cell membrane disorders. [ 28 ] No epidemiological data on HE has been published in China. There are only a few cases and a few series of reports concerning Chinese hereditary elliptocytosis.…”