Researchers have found a genetic explanation for why some human hearts cannot tell left from right.

The team, an interdisciplinary group from the Yale School of Medicine, found a gene that could explain a birth defect that causes hearts to develop without the asymmetries that make most hearts function. This is the first time a genetic marker, the gene NUP188, has been found that explains this birth defect, known as heterotaxy.

“Normally, while we may look symmetric on the outside from left to right, on the inside our organs are placed asymmetrically — so, for example, your heart is placed on the left side, your stomach on the left, your liver is on the right,” said Mustafa Khokha, professor of critical care pediatrics and genetics at the medical school. “And that difference is really critical for the heart because the left side and the right side of the heart pump blood to different places.”

In previous studies, researchers had identified the NUP188 gene as a possible genetic explanation of heterotaxy. But in this most recent effort, researchers used frog models to understand the expression of the gene and its relationship to heterotaxy at the molecular level.

The “NUP” in NUP188 stands for “nuclear porin.” Typically, NUP proteins are embedded in the nuclear membrane and regulate the flow of particles in and out of the nucleus of a cell. Without them functioning properly, most cells are nonviable. However, the team found that NUP188 can also be found in the base of cilia — tail-like structures found in many cells. Defects in the expression of the gene in cilia can help explain heterotaxy. Moreover, the gene’s altered expression in cilia in frogs with heterotaxy did not affect the gene’s function in the nuclear membrane.

Cilia have been implicated in heterotaxy since the 1970s when a study found high co-occurrence of heterotaxy and infertility in men, according to Khokha.

In order to observe the difference in structure, the researcher brought on board School of Medicine professor Joerg Bewersdorf. Bewersdorf’s research focuses on super-resolution microscopy techniques, where a researcher can image microscopic structures that cannot be accurately imaged with typical microscopy.

“Our expectation is that I would form a similar structure both at the nuclear pore and at the cilium base. It would form a channel to allow the passage of molecules between these compartments, but that ended up not being the case,” cell biology professor Patrick Lusk said. “That was a surprise.”

Through super-resolution imaging the researchers were able to find that the protein encircled the base of cilia, unlike its porous form in the cellular membrane. In the mutant variant of NUP188, just the base of the cilia structure was malformed while the porous form was completely unaffected.

One of the major challenges in the research was properly performing the microscopy. The technique itself has challenging elements but also the team needed to be certain of the accuracy of the novel techniques used before presenting them.

“Its a beautiful bridge between clinical impact and basic science,” Bewersdorf said.

Further investigation is required to figure out if the gene is a recessive trait inherited from parents, or if it is a mutation. In addition, the mechanism is still not understood by which the mutant gene affects the cilium.

Surgery is required to treat heterotaxy in the heart.