PRIMARY FAMILIAL POLYCYTHEMIA ASSOCIATED WITH A NOVEL POINT MUTATION IN THE ERYTHROPOIETIN RECEPTOR

Primary familial and congenital polycythaemia (PFCP) is a rare disease characterized by congenital erythrocytosis inherited in an autosomal dominant fashion. Recently, mutations in the erythropoietin receptor ( EpoR) have been identified in PFCP families. We describe a Japanese fa mily with an autosomal dominant inheritance of PFCP. An in vitro colon y assay demonstrated hypersensitivity of erythroid progenitors to eryt hropoietin (Epo) in affected family members. Sequence analysis of RT-P CR products amplified from the C-terminal region of EpoR transcripts i n affected family members revealed that they were all heterozygous for C and T bases at position 5986, which suggested a genetic mutation (C to T) on one allele of EpoR. This mutation gave rise to a translation termination codon TAG at amino acid 435. Thus, the resulting EpoR is a truncated protein product lacking all 74 amino acids downstream of t he mutation. To date, all genetic mutations affecting a family with PF CP, including this one, have been located in the cytoplasmic negative regulatory region of the EpoR. All mutations gave rise to truncated Ep o receptors between Tyrosine 427 and Tyrosine 455. The phosphotyrosine s in this region of EpoR have been demonstrated to be binding sites fo r SHP-1 phosphatase. Therefore PFCP is presumably brought about as a r esult of genetic mutations which cause the loss of the SHP-1 binding s ite in the cytoplasmic region of EpoR.