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An alanine-to-threonine substitution in protein 4.2 cDNA is associated with
a Japanese form of hereditary hemolytic anemia (protein 4.2NIPPON)
EE Bouhassira, RS Schwartz, Y Yawata, K Ata, A Kanzaki, JJ Qiu, RL Nagel and AC Rybicki
Division of Hematology, Albert Einstein College of Medicine-Montefiore
Medical Center, Bronx, NY 10467.
Erythrocyte (RBC) protein 4.2 (P4.2)-deficiency observed in Japanese
individuals results in a hemolytic anemia associated with abnormally shaped
(spherocytic, ovalocytic, and elliptocytic), osmotically fragile RBCs, the
clinical presentation of which resembles hereditary spherocytosis (HS). By
sodium dodecyl sulfate-polyacrylamide gel electrophoresis, P4.2-deficient
individuals contain less than 1% of the normal membrane content of P4.2 and
immunologic analysis shows that the P4.2 present exists as an equimolar
doublet of 74-Kd and 72-Kd bands, in contrast to normal RBC membranes where
a discrete 74-Kd band is not observed. RBC membranes from both of the
biologic parents of a P4.2- deficient individual contained both the 74-Kd
and the 72-Kd bands, demonstrating their heterozygosity for the P4.2
defect. The molecular basis of Japanese P4.2-deficiency was investigated by
reverse transcription of total reticulocyte RNA, followed by polymerase
chain reaction (PCR) amplification, subcloning, and sequencing. The
complete cDNA sequence of a P4.2-deficient patient showed a single point
mutation that changes codon 142 from GCT (alanine) to ACT (threonine)
(Protein 4.2NIPPON). The mutation also eliminated an HgaI restriction site,
therefore allowing rapid screening for the presence of the mutation.
Screening of PCR-amplified genomic DNA showed that the mutation was present
in the homozygous state in four (eight chromosomes) unrelated Japanese
P4.2-deficient individuals and absent in 35 (70 chromosomes) P4.2-normal
controls (including 15 Japanese [30 chromosomes]). The presence of the
mutation was confirmed by allele- specific hybridization. The mutation
occurred in an alternatively spliced exon that is present in two of four
P4.2 mRNA splicing isoforms. These results demonstrate that Japanese
P4.2-deficiency is closely associated with the P4.2 gene and does not arise
secondarily to a defect in another membrane protein, and further suggest
that the P4.2- deficiency is related to the pathogenesis of the hemolytic
anemia in this variant form of recessively inherited spherocytosis.
Volume 79,
Issue 7,
pp. 1846-1854,
04/01/1992
Copyright © 1992 by The American Society of Hematology
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