The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia.

Primary familial and congenital polycythemia (PFCP or familial erythrocytosis) is a rare hematological disorder with either autosomal-dominant inheritance or sporadic occurrence. It is characterized by an increased proliferation of erythroid precursors that results in an elevated red blood cell mass. In some of the PFCP families, the disease phenotype is associated with mutations of the erythropoietin receptor (EPOR). Mutations in other genes are likely to cause PFCP as well, but no evidence so far has been provided to support this contention. In this study, we present a family in which 6 of 15 family members were affected in three generations. We screened exon VIII of the EPOR gene for mutations and found a C-->T substitution (C6148T) in the maternal grandmother of the propositus. The mutated allele of the affected grandmother was not passed to either of her two affected children or to her one healthy child; thus, the disease phenotype was not linked to the C6148T mutation in this family. Further examination of the inheritance of the EPOR gene alleles and sequence analysis ruled out linkage between the disease phenotype and the EPOR gene; therefore, an abnormality in another gene must be the cause of PFCP in this particular family. In three affected family members tested, erythroid progenitors were hypersensitive to EPO. This in vitro behavior of the progenitors confirms the diagnosis of PFCP in these subjects. Moreover, it suggests a dominant lesion of an as-yet unidentified gene, either at the level of the EPOR-signaling pathway or another erythropoiesis-regulating pathway that may be responsible for enhanced proliferation of the erythroid progenitors.