SLC26A9 gene mutations linked to faster CF lung declines: Study

Among 50+ genes identified, SLC26A9 most associated with rapid disease

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

Share this article:

Share article via email
Illustration of a DNA strand.

Additional mutations in the SLC26A9 gene among cystic fibrosis (CF) patients with two copies of F508del — the most common CF-causing mutation in the CFTR gene — were associated with more rapidly declining lung function.

These findings from a study further buttress the idea that variation in genes other than CFTR can modify the course CF takes. Understanding the role of SLC26A9 could help scientists develop new treatments for the genetic condition.

“Gaining a deeper understanding about how SLC26A9 functions as a potential modifier for severe CF-related disease may facilitate personalized medicine approach,” the study’s researchers wrote in “The solute carrier family 26 member 9 modifies rapidly progressing cystic fibrosis associated with homozygous F508del CFTR mutation,” which was published in Clinica Chimica Acta.

CF is caused by mutations in CFTR, leading to no or a faulty CFTR protein, which regulates the balance of salt and water in cells by moving chloride ions into and out of them. A lack of it causes thick and sticky mucus to accumulate in the lungs and other organs, driving the symptoms of CF.

Even among people with the same CF-causing mutation, symptoms and clinical outcomes can vary widely. “Some CF patients live into their 50s, while others with the same mutation die before they turn 18,” Pankaj Agrawal, MD, of the University of Miami Miller School of Medicine and the study’s senior author, said in a university news release.

The reasons for this difference aren’t fully established, but it’s possible that variation in genes other than CFTR might influence how severe the disease becomes.

Previously, the researchers found that certain mutations in epithelial sodium channel genes, namely SCNN1D and SCNN1B, were protective in CF, that patients carrying two copies of F508del who’d survived into their 50s and 60s with minimal declines in lung function dubbed nonprogressive CF had rare mutations in these genes.

Recommended Reading
An illustration of petri dishes.

Mutation type seen to influence global gene activity in CF cell study

Rapidly progressing disease and SLC26A9 variants

Here, researchers looked for genetic variants that might have the opposite effect, leading to worse prognoses and shorter survival.

Genetic sequencing was performed using blood samples from six CF patients with two copies of F508del who had rapidly deteriorating lung function. Three patients received lung transplants before they reached adulthood and three died.

Samples were also analyzed from more than 3,000 people without CF along with eight with nonprogressive CF from the previous study.

Among more than 50 candidate genes identified in the screening, SLC26A9 was recognized as the one most significantly associated with rapidly progressing CF. Three of the six CF patients carried variants in that gene, while none of the eight with more stable CF had such a mutation.

Of the two mutations identified, one of which affected two patients, both were predicted to have harmful effects on the function of the SLC26A9 protein produced from the gene.

Finding that a mutation in this gene could contribute to CF symptom severity “makes a lot of sense,” given that SLC26A9 is found at high levels in the lungs and is responsible for chloride transport, much like CFTR, Agrawal said.

Normally, SLC26A9 activity in certain lung cells might help compensate for the loss of CFTR in CF patients, but these mutations could mean that neither protein is working as it should.

“It’s likely a double whammy and patients who have mutations in both CFTR and this gene have much worse outcomes,” Agrawal said.

SLC26A9 has also been shown to modify CF-related diabetes, bowel obstructions, and responses to CF therapies, said the researchers, who believe the findings offer new insights into therapeutic strategies for CF. While there are highly effective CFTR modulators available to most patients, additional treatments that target other genes that modify the disease course could offer more benefit.

“We need to identify more genes that may be playing a role in these conditions,” Agrawal said. “Once we’ve done that, we can start testing potential therapies that target those genes. There are many opportunities to explore.”