Scientists from Norway and Switzerland uncovered for the first time a mutation in EPO, the gene encoding erythropoetin, as the genetic cause of an autosomal dominantly inherited form of erythrocytosis in a family with 10 affected members in four generations. The patients presented with symptoms of headache and dizziness and had increased hemoglobin levels and elevated erythropoietin concentrations in serum. The researchers performed genome-wide linkage analysis and then targeted sequencing of 215 genes and identified a heterozygous single-nucleotide deletion in EPO leading to a frameshift that interrupts translation of the transcript. This would suggest a loss of protein function, but, instead, subsequent functional analyses using for example CRISPR technology revealed a surprising scenario: As a result of the mutation another, normally noncoding mRNA is transcribed from an alternative promoter, producing a biologically active erythropoietin which causes the phenotype of an EPO overproduction. The researchers confirmed their results in a second family who also carried a single-nucleotide deletion in EPO.

The results of this study were published in The New England Journal of Medicine.