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Band 3 Tuscaloosa: Pro327----Arg327 substitution in the cytoplasmic domain
of erythrocyte band 3 protein associated with spherocytic hemolytic anemia
and partial deficiency of protein 4.2
P Jarolim, J Palek, HL Rubin, JT Prchal, C Korsgren and CM Cohen
Department of Biomedical Research, St. Elizabeth's Hospital of Boston,
Tufts University School of Medicine, MA 02135.
Protein 4.2 is a major red blood cell (RBC) protein that interacts with the
band 3 protein and with ankyrin. Inherited deficiencies of this protein are
associated with spherocytic hemolytic anemia, but the molecular basis of
this defect is unknown. We have studied the underlying defect in a patient
with spherocytic hemolytic anemia whose RBCs had a partial (29% +/- 5%)
deficiency of protein 4.2. We have first studied the binding of normal
ankyrin and protein 4.2 to patient inside-out vesicles (IOVs) stripped of
peripheral proteins. While the binding of ankyrin was normal, the predicted
maximal binding capacity of patient IOVs for band 4.2 was 20% to 33% lower
than that of control IOVs, suggesting a defect in the cytoplasmic domain of
band 3 (cdb3). An additional line of evidence pointing to a possible
abnormality of band 3 was an abnormal proteolytic digest of cdb3. To
elucidate the underlying molecular defect, we have cloned and sequenced the
cDNA coding for cdb3 from the patient. One band 3 allele was found to be
normal, while clones corresponding to the other allele contained two
mutations: substitution A----G in nucleotide 166, changing codon 56 from
AAG to GAG (Lys----Glu), and substitution C----G in nucleotide 980,
changing codon 327 from CCC to CGC (Pro----Arg). Since the Lys56--- -Glu56
substitution is found in a common asymptomatic variant of the band 3
protein designated band 3 Memphis, we conclude that either the
Pro327----Arg327 substitution itself, or in combination with the band 3
Memphis polymorphism, underlies the abnormal binding of protein 4.2 to cdb3
and results in the spherocytic phenotype.
Volume 80,
Issue 2,
pp. 523-529,
07/15/1992
Copyright © 1992 by The American Society of Hematology
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