Researchers Identify a Second Cystic Fibrosis Genetic Culprit

Medical illustration of the human lungs
Article Summary
  • Cystic fibrosis patients with the DeltaF508 mutation often experience dramatically different health outcomes, with some living into their 50s and others dying prior to 18 years old.
  • Dr. Pankaj Agrawal published a study that analyzed variants in the SLC26A9 gene that can worsen cystic fibrosis outcomes.
  • The study revealed three of the six patients in the study had a SLC26A9 gene mutation, and those three patients all had severe cystic fibrosis.

Caused by mutations in the CFTR gene, cystic fibrosis (CF) affects multiple organs, particularly the lungs. While the condition has been heavily studied, a number of mysteries remain, including why patients with the most common DeltaF508 mutation in the CFTR gene can have radically different outcomes.

Researchers at the University of Miami Miller School of Medicine and other schools have shown that variants in a related gene, SLC26A9, can worsen CF. The study was published in the journal Clinica Chimica Acta last week.

“Some CF patients live a long time, into their 50s, while others with the same mutation die before they turn 18,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School Department of Pediatrics and Jackson Health System and senior author on the paper. “Now, we know there are mutations in other genes that are making this disease protective or damaging in individual patients.”

Mutations that Affect Cystic Fibrosis

CFTR mutations affect chloride channels in cells that govern the flow of chloride and water. The end result is thick mucus in the lungs and other organs that can impair breathing and cause infections, gastrointestinal problems and many other health issues.

In a previous study published in 2017, Dr. Agrawal and colleagues found mutations in epithelial sodium channel genes, or ENaCs (SCNN1D and SCNN1B), were protective, helping CF patients live longer. The current study addresses the other side of the coin: mutations that worsen CF and shorten lifespan.

Miller School of Medicine pediatrician Dr. Pankaj Agarwal
Dr. Pankaj Angrawal was senior author on a study that showed variants in the SLC26A9 gene can worsen cystic fibrosis.

The team studied six patients with the F508del variant whose lungs were rapidly deteriorating. By sequencing these patients’ exomes, the 2% of genomes that code for proteins, the researchers found a mutation in SLC26A9 that seems to deter patient prognoses. Three of the six patients with severe disease had SLC26A9 variations.

“This makes a lot of sense because SLC26A9 is highly expressed in the lungs and is responsible for chloride transport, just like CFTR,” said Dr. Agrawal. “It’s likely a double whammy and patients who have mutations in both CFTR and this gene have much worse outcomes.”

The Complexity of CFTR

These findings, combined with the results from the earlier study, paint a complex picture of how CFTR interacts with related genes. While there are effective medications now that can help restore CFTR function and mitigate symptoms, new treatments that target SLC26A9 (or ENaCs) could provide further therapeutic benefit.

Identifying patients with SLC26A9 variants could alert clinicians of an aggressive disease path. This study also presents the possibility that well-known, disease-driving genes may be accompanied by other genes that improve or worsen outcomes.

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

Tags: cystic fibrosis, Dr. Pankaj Agrawal, genetic variants, genetics, neonatology