Inherited mutation leads to overproduction of EPO

March 9, 2018, University of Basel
Inheritance of the familial erythrocytosis. Credit: University of Basel, Department of Biomedicine

A newly discovered hereditary mutation is responsible for an increased production of erythropoietin (EPO) in the blood. This mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins to be reprogrammed so that it produces EPO, thus abnormally increasing the number of red blood cells. Researchers from the Department of Biomedicine at the University of Basel and University Hospital Basel reported these findings in The New England Journal of Medicine.

In patients suffering from erythrocytosis, the mass (erythrocytes) is exceptionally high. The disease is usually triggered by a genetic disorder in the bone marrow, which leads to increased production of red cells.

Researchers from the University of Basel and University Hospital Basel have now identified the first mutation in the EPO gene in a family with hereditary erythrocytosis. Ten affected family members from four generations took part in the study.

Using a genome-wide linkage analysis and gene sequencing, the researchers discovered that all of the affected family members lacked a single base in the EPO gene. As the EPO hormone increases the production of red blood cells, it was likely that this mutation caused the disease.

However, the researchers were initially puzzled. This mutation would actually lead to a loss of function of the EPO gene, because the absence of the base shifts the reading frame of the genetic code, meaning that no more EPO protein can be formed. Despite this, the concentration of EPO hormone in the patients' blood measurably increased rather than decreased.

The explanation was found using the CRISPR method, which allowed the researchers to engineer carrying the EPO mutation. There is a second, hidden mRNA in the EPO gene that is not normally involved in the production of a protein. As the researchers show, the mutation also leads to a shift in the reading frame of this second mRNA, this time with the result that more biologically active EPO hormone is produced.

"The mechanism is intriguing," says study leader Professor Radek Skoda from the University of Basel's Department of Biomedicine. "The mutation reprograms the gene product so that it gains a new function and is misused to overproduce EPO." With consequences for the patients, who suffer from headaches and dizziness thanks to the increased red blood mass.

Mutations in the EPO gene should be taken into account in future searches for the causes of hereditary erythrocytosis, write the researchers in The New England Journal of Medicine.

Explore further: Team reports progress in pursuit of sickle cell cure

More information: Jakub Zmajkovic et al, A Gain-of-Function Mutation in EPO in Familial Erythrocytosis, New England Journal of Medicine (2018). DOI: 10.1056/NEJMoa1709064

Related Stories

Team reports progress in pursuit of sickle cell cure

February 16, 2018
Scientists have successfully used gene editing to repair 20 to 40 percent of stem and progenitor cells taken from the peripheral blood of patients with sickle cell disease, according to Rice University bioengineer Gang Bao.

The toxic relationship between ALS and frontotemporal dementia

February 5, 2018
ALS and frontotemporal dementia (FTD) are two neurodegenerative diseases with a toxic relationship, according to a new USC Stem Cell study published in Nature Medicine.

New genetic mutation that causes male infertility discovered

August 3, 2017
Researchers at Ben-Gurion University of the Negev and Soroka University Medical Center in Beer-Sheva, Israel have discovered a new genetic mutation that prevents sperm production.

Genome therapy could lead to new treatment for life-threatening blood disorders

July 17, 2017
Genome therapy with beneficial natural mutation could lead to new treatment for life-threatening blood disorders

Bone disease traced to the Middle Ages

June 19, 2017
The special form of the bone disease osteopetrosis that exists in Västerbotten is due to a gene mutation that can be traced back to the Middle Ages and leads to defective bone resorption, according to new research led at ...

Family members without inherited mutation have increased risk of melanoma

December 8, 2017
In families who carry certain inherited mutations that increase the risk for melanoma, members who do not carry the mutation also have an increased risk of melanoma, a study from Karolinska Institutet published in Genetics ...

Recommended for you

Geneticists make new discovery about how a baby's sex is determined

December 14, 2018
Medical researchers at Melbourne's Murdoch Children's Research Institute have made a new discovery about how a baby's sex is determined—it's not just about the X-Y chromosomes, but involves a 'regulator' that increases ...

Scientists identify method to study resilience to pain

December 14, 2018
Scientists at the Yale School of Medicine and Veterans Affairs Connecticut Healthcare System have successfully demonstrated that it is possible to pinpoint genes that contribute to inter-individual differences in pain.

CRISPR joins battle of the bulge, fights obesity without edits to genome

December 13, 2018
A weighty new study shows that CRISPR therapies can cut fat without cutting DNA. In a paper published Dec. 13, 2018, in the journal Science, UC San Francisco researchers describe how a modified version of CRISPR was used ...

Noncoding mutations contribute to autism risk

December 13, 2018
A whole-genome sequencing study of nearly 2,000 families has implicated mutations in 'promoter regions' of the genome—regions that precede the start of a gene—in autism. The study, which appears in the December 14 issue ...

New method for studying ALS more effectively

December 13, 2018
The neurodegenerative disease ALS causes motor neuron death and paralysis. However, long before the cells die, they lose contact with muscles as their axons atrophy. Researchers at Karolinska Institutet in Sweden have now ...

Paternal grandfather's high access to food may indicate higher mortality risk in grandsons

December 12, 2018
A paternal grandfather's access to food during his childhood is associated with mortality risk, especially cancer mortality, in his grandson, shows a large three-generational study from Stockholm University. The reason might ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.