PRIMARY FAMILIAL POLYCYTHEMIA - A FRAMESHIFT MUTATION IN THE ERYTHROPOIETIN RECEPTOR GENE AND INCREASED SENSITIVITY OF ERYTHROID PROGENITORS TO ERYTHROPOIETIN

Primary familiar and congenital polycythemia (PFCP) is characterized b y erythrocytosis with normal arterial PO2, blood P-50, and serum eryth ropoietin (EPO) levels. In two PFCP families EPO receptor (EPOR) polym orphisms cosegregated with PFCP. A heterozygous insertion of G at EPOR nucleotide 5975 was identified in genomic DNA from polycythemic membe rs of family no. 2, 5974insG shifts the reading frame at codon 430, pr edicting amino acid substitutions and truncation of the last 64 amino acids. Wild-type and mutant EPOR transcripts were detected in erythroi d 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 fun ctional effect of this EPOR mutation was directly compared with the ot her C-terminal mutations reported in unrelated PFCP families by expres sion in Ba/F3 cells. The transfected cells with another primary polycy themia associated EPOR mutant construct (G6002A) also exhibited increa sed sensitivity to EPO. (C) 1995 by The American Society of Hematology .