Characteristic features of the genotype and phenotype of hereditary spherocytosis in the Japanese population

Hereditary spherocytosis (HS) is the most common hemolytic anemia of congen ital origin in the Japanese population. Among 844 cases of 520 kindred with congenital red cell membrane disorders studied at: the Kawasaki Medical Sc hool in the last 25 years (1975-1999), 407 cases (48.2%) of 215 kindred had HS. Among the recent: 60 kindred with HS, autosomal dominant (AD) transmis sion was proven in 19. The remaining 41 non-AD I-IS included 1) homozygous patients with autosomal recessive inheritance, 2) HS patients with de novo gene mutations, and 3) mild HS with AD inheritance. The extent of clinical severity in the non-AD HS cases was nearly identical to that in the AD case s. The incidence of membrane protein abnormalities in our 60 Japanese HS ki ndred was unique: there were lower ankyrin deficiencies (7%), moderate band 3 deficiencies (20%), and much higher protein 4.2 deficiencies (45%), with 28% of unknown etiology. The incidence of membrane protein deficiencies co rresponded to that determined by gene analyses; ie, mutations mostly in ban d 3 and/or in protein 4.2 genes and fewer ankyrin gene mutations. In the ba nd 3 gene, 11 mutations pathognomonic for HS were identified (3 frameshift and 8 missense mutations). There were 5 mutations of the protein 4.2 gene ( 3 missense mutations, 1 nonsense mutation, and 1 splicing mutation) pathogn omonic for HS. On the other hand, 2 missense mutations were detected in the ankyrin gene in this study. The genetic abnormalities in our HS patients c orrelated well with the phenotypic ultrastructural abnormalities of red cel l membranes in situ. Ankyrin mutations (ankyrin Marburg and ankyrin Stuttga rt with frameshift mutations) were associated mostly with a disrupted cytos keletal network, and band 3 mutations (band 3 Kagoshima with frameshift mut ation) typically demonstrated anomalies of intramembrane particles (IMPs). Protein 4.2 mutations (homozygotes of protein 4.2 Nippon) with complete pro tein 4.2 deficiency showed abnormalities of both the cytoskeletal network a nd IMPs. (C) 2000 The Japanese Society of Hematology.