A Gain-of-Function Mutation in EPO in Familial Erythrocytosis

N Engl J Med. 2018 Mar 8;378(10):924-930. doi: 10.1056/NEJMoa1709064.

Abstract

Familial erythrocytosis with elevated erythropoietin levels is frequently caused by mutations in genes that regulate oxygen-dependent transcription of the gene encoding erythropoietin ( EPO). We identified a mutation in EPO that cosegregated with disease with a logarithm of the odds (LOD) score of 3.3 in a family with autosomal dominant erythrocytosis. This mutation, a single-nucleotide deletion (c.32delG), introduces a frameshift in exon 2 that interrupts translation of the main EPO messenger RNA (mRNA) transcript but initiates excess production of erythropoietin from what is normally a noncoding EPO mRNA transcribed from an alternative promoter located in intron 1. (Funded by the Gebert Rüf Foundation and others.).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Erythropoietin / biosynthesis
  • Erythropoietin / genetics*
  • Female
  • Frameshift Mutation*
  • Gain of Function Mutation*
  • Gene Deletion
  • Genes, Dominant
  • Genetic Linkage
  • Humans
  • Male
  • Microsatellite Repeats
  • Pedigree
  • Polycythemia / congenital*
  • Polycythemia / genetics
  • Protein Biosynthesis
  • RNA, Messenger / metabolism

Substances

  • EPO protein, human
  • RNA, Messenger
  • Erythropoietin

Supplementary concepts

  • Polycythemia, primary familial and congenital