Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III

Hereditary spherocytosis (HS) is an inherited haemolytic anaemia, character ized by spheroidal, osmotically fragile red blood cells, This disorder exhi bits heterogeneity in terms of both clinical severity and underlying molecu lar defect. We have studied a South African Cape Coloured individual with s evere IIS owing to a band 3 deficiency caused by two mutations, occurring i n trans, in the band 3 gene: a novel variant that we have designated band 3 Cape Town and a previously described mutation, band 3 Prague III. Analysis of erythrocyte membrane proteins indicated a deficiency of both band 3 and protein 4.2, as well as a decreased functional capacity of band 3 to trans port anions. Band 3 Cape Town is defined by a GAG --> AAG point mutation at codon 90, substituting a glutamic acid with a lysine in the cytoplasmic do main of the molecule, while band 3 Prague III is a codon 870 CGG --> TGG po int mutation, replacing an arginine with a tryptophan in the transmembrane region of band 3. mRNA is transcribed from both mutant alleles, implying th at mutant proteins are synthesized, but are either degraded prior to membra ne incorporation or insertion is impaired. We conclude that the combination of these two mutations exacerbated the clinical presentation of the proban d.