Familial Erythrocytosis Linked to EPO Gene Mutation

Mutations in the erythropoietin receptor or in oxygen-sensing genes have been associated with erythrocytosis. To determine if gain-of-function mutations in the EPO gene are also associated with this condition, investigators analyzed the EPO gene of 10 family members in four generations with familial erythrocytosis. Their symptoms of headache and dizziness were associated with hemoglobin levels >18 g/dL in men and >16 g/dL in women, and all had levels of erythropoietin that were elevated relative to hemoglobin concentration.

Gene sequencing revealed a single-base deletion in exon 2 of the EPO gene (c.32delG). The deletion created a frameshift that truncated the signal peptide and converted a noncoding mRNA, originally transcribed from an alternative promoter within EPO intron 1, into an mRNA that produced functional erythropoietin protein. This mRNA had a longer half-life than wild-type mRNA, and its increased stability was probably responsible for the elevated erythropoietin

production; the main site of production was the liver, not the kidney.