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Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia
and a homozygous 40glutamic acid-->lysine substitution in the
cytoplasmic domain of band 3 (band 3Montefiore)
AC Rybicki, JJ Qiu, S Musto, NL Rosen, RL Nagel and RS Schwartz
Division of Hematology, Albert Einstein College of Medicine/Montefiore
Medical Center, Bronx, NY 10467.
Red blood cell (RBC) protein 4.2 deficiency is often associated with a
moderate nonimmune hemolytic anemia, splenomegaly, and osmotically fragile
RBCs resembling, but not identical to, hereditary spherocytosis (HS). In
the Japanese type of protein 4.2 deficiency (protein 4.2Nippon), the anemia
is associated with a point mutation in the protein 4.2 cDNA. In this
report, we describe a patient with moderate and apparently episodic
nonimmune hemolytic anemia with splenomegaly, spherocytosis, osmotically
fragile RBCs, reduced whole cell deformability, and abnormally dense cells.
Sodium dodecyl sulfate- polyacrylamide gel electrophoresis analysis of the
proposita's RBC membrane proteins showed an 88% deficiency of protein 4.2
and a 30% deficiency of glyceraldehyde-3-phosphate dehydrogenase (band 6).
Structural and molecular analyses of the proposita's protein 4.2 were
normal. In contrast, limited tryptic digestion of the proposita's band 3
showed a homozygous abnormality in the cytoplasmic domain. Analysis of the
pedigree disclosed six members who were heterozygotes for the band 3
structural abnormality and one member who was a normal homozygote. Direct
sequence analysis of the abnormal band 3 tryptic peptide suggested that the
structural abnormality resided at or near residue 40. Sequence analysis of
the proposita's band 3 cDNA showed a 232G-->A mutation resulting in a
40glutamic acid-->lysine substitution (band 3Montefiore).
Allele-specific oligonucleotide hybridization was used to probe for the
mutation in the pedigree, showing that the proposita was homozygous, and
the pedigree members who were heterozygous for the band 3 structural
abnormality were also heterozygous for the band 3Montefiore mutation. The
band 3Montefiore mutation was absent in 26 chromosomes from race-matched
controls and in one pedigree member who did not express the band 3
structural abnormality. In coincidence with splenectomy, the proposita's
anemia was largely corrected along with the disappearance of most
spherocytes and considerable improvements of RBC osmotic fragility, whole
cell deformability, and cell density. We conclude that this hereditary
hemolytic anemia is associated with the homozygous state for band
3Montefiore (40glutamic acid-->lysine) and a decreased RBC membrane
content of protein 4.2. We speculate that band 3 structural abnormalities
can result in defective interactions with protein 4.2 and band 6, and in
particular, that the region of band 3 containing 40glutamic acid is
involved directly or indirectly in interactions with these proteins.
Volume 81,
Issue 8,
pp. 2155-2165,
04/15/1993
Copyright © 1993 by The American Society of Hematology
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