Image of a heart with a DNA double helix in front of it to indicate genetic heart diseases such as familial hypercholesterolemia.
Credit: iStock/SvetaP DNA double helix: iStock/Kagenmi

The effects of a genetic variant that normally causes early embryo death due to a defective heart can be overcome if a protective gene variant is also present, suggest the results of a University of Pittsburgh study.

The researchers were studying a rare mutation in the gene TPM1, in eight people with a large atrial septal defect (ASD) in the heart, otherwise known as a ‘hole in the heart’, but who still had functional cardiac capacity. To study the mutation further, the team created a mouse model with the mutation present in mouse eggs.

After fertilization and implantation, all the mouse embryos with the TPM1 mutation died within a week. However, the humans with the mutation had functional, if slightly defective hearts. The researchers confirmed the viability of the cardiac cells of these individuals by culturing them in the lab showing that a beat was also present in the mature cells.

The extreme rarity of the TPM1 variant in humans, it’s been found in less than 20 people around the world, suggests it should be lethal in them as well as mice, but a small number of people who have the mutation do survive and have functional if weakened hearts.

“This gene is clearly very deleterious—the mice did not even develop a heartbeat, let alone survive to birth,” said Cecilia Lo, distinguished professor and F. Sargent Cheever Chair of Pitt’s Department of Developmental Biology, who led the research, in a press statement. “That led us to wonder: How are people who we know have this gene walking around?”

The answer is that they are carriers of another ‘protective’ gene variant in a gene called TLN2, which encodes a protein that plays an important role in the function of heart muscle like TPM1. The TLN2 mutation was co-expressed in beating heart cells with the TPM1 variant and seemed to reduce the pathogenic effect of the TPM1 variant considerably, if not completely.

A few other possible protective mutations were found by the researchers, but the TLN2 one was the only one co-expressed in the beating heart cells with the TPM1 variant.

“These findings provide a paradigm for how protective variants can increase genetic resiliency. Oligogenic inheritance of multiple pathogenic variants has been shown to cause congenital heart diseases and cardiomyopathies. While such studies showed multiple pathogenic variants can contribute to disease, our study showed pathogenic and protective variants in combination can provide the stable heritable transmission of an otherwise lethal mutation,” write the researchers in the journal Cell Reports Medicine.

The team then created a mouse model with both the pathogenic and protective mutations and, similar to in the human carriers, the mice had functional beating hearts, albeit with noticeable atrial septal defects.

The researchers are not sure how widespread this phenomenon of pathogenic genes pairing with protective ones is, but say that their findings shed a new light on the field of human genetics and genetic disease. “The future of genetic therapy doesn’t have to be about turning off bad genes. It can also be about turning on good ones.”

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