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Primary familial polycythemia: a frameshift mutation in the erythropoietin
receptor gene and increased sensitivity of erythroid progenitors to
erythropoietin
L Sokol, M Luhovy, Y Guan, JF Prchal, GL Semenza and JT Prchal
Division of Hematology/Oncology, University of Alabama at Birmingham 35294,
USA.
Primary familial and congenital polycythemia (PFCP) is characterized by
erythrocytosis with normal arterial PO2, blood P50, and serum
erythropoietin (EPO) levels. In two PFCP families EPO receptor (EPOR)
polymorphisms cosegregated with PFCP. A heterozygous insertion of G at EPOR
nucleotide 5975 was identified in genomic DNA from polycythemic members of
family no. 2. 5974insG shifts the reading frame at codon 430, predicting
amino acid substitutions and truncation of the last 64 amino acids.
Wild-type and mutant EPOR transcripts were detected in erythroid
progenitors from affected individuals. Burst-forming units- erythroid from
patients exhibited increased colony size and sensitivity to EPO.
Transfected Ba/F3 cells expressing EPOR 5974insG exhibited increased EPO
sensitivity compared with cells expressing wild-type EPOR. The functional
effect of this EPOR mutation was directly compared with the other
C-terminal mutations reported in unrelated PFCP families by expression in
Ba/F3 cells. The transfected cells with another primary polycythemia
associated EPOR mutant construct (G6002A) also exhibited increased
sensitivity to EPO.
Volume 86,
Issue 1,
pp. 15-22,
07/01/1995
Copyright © 1995 by The American Society of Hematology
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