Characterization of 13 novel band 3 gene defects in hereditary spherocytosis with band 3 deficiency

Abstract

Hereditary spherocytosis (HS) is a common hemolytic anemia of variable clinical expression. Pathogenesis of HS has been associated with defects of several red cell membrane proteins including erythroid band 3. We have studied erythrocyte membrane proteins in 166 families with autosomal dominant HS. We have detected relative deficiency of band 3 in 38 kindred (23%). Band 3 deficiency was invariably associated with mild autosomal dominant spherocytosis and with the presence of pincered red cells in the peripheral blood smears of unsplenectomized patients. We hypothesized that this phenotype is caused by band 3 gene defects. Therefore, we screened band 3 DNA from these 38 kindred for single strand conformational polymorphisms (SSCP). In addition to five mutations detected previously by SSCP screening of cDNA, we detected 13 new band 3 gene mutations in 14 kindred coinherited with HS. These novel mutations consisted of two distinct subsets. The first subset included seven nonsense and frameshift mutations that were all associated with the absence of the mutant mRNA allele from reticulocyte RNA, implicating decreased production and/or stability of mutant mRNA as the cause of decreased band 3 synthesis. The second group included five substitutions of highly conserved amino acids and one in-frame deletion. These six mutations were associated with the presence of comparable levels of normal and mutant band 3 mRNA. We suggest that these mutations interfere with band 3 biosynthesis leading thus to the decreased accumulation of the mutant band 3 allele in the plasma membrane.

Genotype–phenotype correlation in children with hereditary spherocytosis

“…Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia, affecting up to 1/2000 individuals of northern European ancestry 1 . Pathogenic mutations in five genes that code for red blood cell (RBC) membrane‐anchoring and cytoskeleton proteins [ ANK1 (ankyrin), SPTB (β‐spectrin), SPTA1 (α‐spectrin), SLC4A1 (band‐3) and EPB42 (protein 4·2)] have been described as causative for HS 2–6 . Mutations in these genes lead to abnormal membrane‐anchoring, resulting in a disruption of the RBC's biconcave disc shape and gradual loss of the red cell membrane, thereby transforming red cells into spherocytes.…”

Substitution Glu480Lys in erythroid band 3 corresponds to the Fra blood group antigen and supports existence of the second ectoplasmic loop of band 3

“…Band‐3 mutations have been implicated in the pathogenesis of South‐east Asian ovalocytosis, 4‐6 hereditary spherocytosis, 7 congenital acanthocytosis, 8 and distal renal tubular acidosis 9,10 . Mutations leading to band‐3 disorders have recently been reviewed 11 .…”

Anemias hemolíticas

“…• Deficiência da Banda 3: as duas principais funções dessa banda são promover a coesão entre o plasma da célula vermelha e o citoesqueleto para prevenir perdas e trocar íons para manter a água dentro da célula e prevenir contra a desidratação. Com a deficiência, perdem--se essas propriedades, facilitando a esferocitose (JAROLIM; MURRAY; RUBIN et al, 1996).…”