A mutant protein responsible for most cases of cystic fibrosis is too busy “talking” to the wrong neighbors to do its job properly, according to research published online in the journal Nature.

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In cystic fibrosis, faulty protein interactions can cause life-threatening issues.

The Centers for Disease Control and Prevention (CDC) describe cystic fibrosis (CF) as a “chronic, progressive, and frequently fatal inherited disease of the body’s mucus glands.”

It primarily affects the respiratory and digestive systems in children and young adults, and usually involves the sweat glands and the reproductive system, too.

People born with CF have an average lifespan of around 30 years.

CF stems from an abnormality in the glands that produce sweat and mucus. The symptoms and impact are widely variable.

Sweat cools the body; mucus lubricates the respiratory, digestive and reproductive systems and protects against infection by preventing tissues from drying out.

People with CF lose high amounts of salt when they sweat, which can upset the balance of minerals in the blood, leading to abnormal heart rhythms. Going into shock is also a risk.

Mucus in CF patients is very thick and accumulates in the intestines and lungs. The result is persistent infections, malnutrition, poor growth, respiratory difficulties and eventually permanent lung damage. Most patients will die of lung disease.

Fast facts about cystic fibrosis
  • 30,000 Americans have CF, mostly white people of European origin
  • Around 2,500 babies are born in the US each year with CF
  • 1 in 12 people, or 12 million people in the US are thought to be carriers.

Learn more about cystic fibrosis

Other medical problems include sinusitis, nasal polyps, clubbing of fingers and toes, rupture of lung tissue, coughing of blood, enlargement of the right side of the heart, abdominal pain and discomfort, rectal prolapse, liver disease, diabetes, inflammation of the pancreas and gallstones.

Symptoms can be treated, but so far, no therapy can prevent or reverse CF or fully restore lung function.

The only solution would be gene therapy at an early age to repair or replace the defective gene, or resolving the missing interactions in mutant proteins.

Co-first author Casimir Bamberger and colleagues at The Scripps Research Institute (TSRI) believe a better understanding of a protein called the CF transmembrane conductance regulator (CFTR) could be the key.

Most patients with CF have a mutation, called ∆F508, in the gene that encodes CFTR, keeping CFTR from folding properly and being processed correctly in cells.

The researchers analyzed cell samples using Co-Purifying Protein Identification Technology (CoPIT), a method they developed to identify proteins and analyze data.

CoPIT enabled the team to identify and track nearly every protein CFTR interacted with, even the secondary and tertiary ones.

They were surprised to find that the ∆F508 CFTR mutant had acquired an entirely new “disease-specific” interaction network.

Co-first author Sandra Pankow says:

“Three hundred proteins changed their level of interaction, and an additional 200 proteins interacted with the mutated CFTR. It’s like the wrong people are talking to the mutated CFTR all the time.”

The researchers narrowed these mutant protein interactions down to eight key disruptive proteins and then used a gene silencing approach to remove those proteins and block their interaction with ∆F508 CFTR.

Removing the chatter of the additional interactions partially restored ∆F508 CFTR’s normal function, suggesting that therapies could one day treat the root cause of cystic fibrosis.

Interestingly, previous studies have shown that mutant CFTR regains normal functions at low temperatures.

Freezing people is clearly not practical, but the concept behind the study could help find new drug candidates that could mimic what happens at low temperatures.

Bamberger believes that the interactions identified “really fuel the pipeline for new drug targets to treat cystic fibrosis.”

The authors say the next step is to look for small molecule drug candidates that could target the disruptive proteins.

Medical News Today recently reported on gene therapy that could help people with CF.