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 erythro cytosis) is a rare proliferative disorder of erythroid progenitor cell s, characterized by elevated erythrocyte mass and hemoglobin concentra tion, 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; mo st of these mutations resulted in the truncation of the COOH-terminal of the EPOR protein. We studied, a family with autosomal dominant inhe ritance of PFCP in which four subjects were affected in three generati ons. We screened the affected individuals for EPOR gene mutations usin g 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 exhib ited hypersensitive EPO-dependent proliferation compared to the wild-t ype EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1), We also examined the segregation of the mutation with P FCP in the family and found that a child in the third generation inher ited the mutation without having laboratory evidence of polycythemia. Further in vitro analysis of the erythroid progenitor cells of this af fected child revealed that the progenitor cells were hypersensitive to EPO (a hallmark of PFCP) suggesting the presence of the disease at th e level of progenitor cells. Failure of this child to develop polycyth emia suggests the existence of as yet unidentified environmental or ge netic factors that map suppress disease development.