Researchers say they have discovered a mutation associated with hereditary erythrocytosis.
The mutation causes a messenger RNA (mRNA) that is not normally involved in the formation of proteins to be reprogrammed so that it produces erythropoietin (EPO), thereby abnormally increasing red blood cell production.
Radek Skoda, MD, of the University of Basel in Switzerland, and his colleagues described this discovery in NEJM.
The team found the mutation in a family with hereditary erythrocytosis. The researchers studied 10 affected family members spanning 4 generations.
Genome-wide linkage analysis and gene sequencing revealed a heterozygous single-base deletion in exon 2 of EPO (chromosome 7: 100,319,199 GG→G) in all 10 affected family members.
However, the researchers were initially puzzled. This c.32delG mutation should 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.
To investigate this, the researchers used CRISPR to engineer cells carrying the c.32delG mutation. In this way, they found a second, hidden mRNA in the EPO gene that is not normally involved in the production of a protein.
The c.32delG mutation also leads to a shift in the reading frame of this second mRNA, with the result that more biologically active EPO hormone is produced.
“The mechanism is intriguing,” Dr Skoda said. “The mutation reprograms the gene product so that it gains a new function and is misused to overproduce EPO.”