Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.

Primary familial and congenital polycythemia (PFCP or familial erythrocytosis) is a rare proliferative disorder of erythroid progenitor cells, characterized by elevated erythrocyte mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to erythropoietin (EPO), and autosomal dominant inheritance or sporadic occurrence. A number of EPO receptor (EPOR) mutations were found in subjects with PFCP; most of these mutations resulted in the truncation of the COOH-terminal of the EPOR protein. We studied a family with autosomal dominant inheritance of PFCP in which four subjects were affected in three generations. We screened the affected individuals for EPOR gene mutations using SSCP analysis and found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids. The mutant C5964G-EPOR exhibited hypersensitive EPO-dependent proliferation compared to the wild-type EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1). We also examined the segregation of the mutation with PFCP in the family and found that a child in the third generation inherited the mutation without having laboratory evidence of polycythemia. Further in vitro analysis of the erythroid progenitor cells of this affected child revealed that the progenitor cells were hypersensitive to EPO (a hallmark of PFCP) suggesting the presence of the disease at the level of progenitor cells. Failure of this child to develop polycythemia suggests the existence of as yet unidentified environmental or genetic factors that may suppress disease development.