A Gain-of-Function Mutation in EPO in Familial Erythrocytosis
Open accessAbstract
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.).
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PTVs in EPO are a well-established cause of erythrocytosis.
“PTVs in this gene are a well-established cause of erythrocytosis57.”
From Rare variant associations with plasma protein levels in the UK Biobank (2023) · cites this paper as [57]
The Summary and Discussion describe two EPO frameshift variants associated with familial erythrocytosis. But the paper presents them as a newly identified, unusual gain-of-function mechanism—not as evidence that protein-truncating variants in EPO are a well-established cause of erythrocytosis. The discussion on p. 930 says EPO mutations should be considered when investigating inherited erythrocytosis. (LLM, conf=0.88)
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Rare variant associations with plasma protein levels in the UK Biobank
Dhindsa, R. S., Burren, O. S., Sun, B. B., Prins, B. P., Matelska, D., Wheeler, E., Mitchell, J., Oerton, E., Hristova, V. A., Smith, K. R., et al. (2023) · Nature · doi:10.1038/s41586-023-06547-x · Cited by 193 · see citing works
- Authors
- Zmajkovic, J., Lundberg, P., Nienhold, R., Torgersen, M. L., Sundan, A., Waage, A., & Skoda, R. C.
- Affiliations
- University of Basel (CH)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-03-08
- Volume
- 378
- Issue
- 10
- Pages
- 924-930
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2793239896
- Cited by
- 56
- References
- 1
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 2
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A-147016/1, 31003A_166613)
- Krebsliga Schweiz (KFS-3655-02-2015, KLS-2950-02-2012)
- Central Norway Regional Health Authority (Biobank Research 2011 to AW)
- Gebert Rüf Stiftung (GRS-045/09)
- Topics
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Keywords
- familial erythrocytosis, erythropoietin, gain-of-function mutations, frameshift mutation, alternative promoters, intron 1, co-segregation
- MeSH terms
- Gain of Function Mutation, Erythropoietin, Female, Genes, Dominant, Humans, Genetic Linkage, Male, Pedigree, Polycythemia, RNA, Messenger, Protein Biosynthesis, Frameshift Mutation, Gene Deletion, Microsatellite Repeats, Clustered Regularly Interspaced Short Palindromic Repeats
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