Gene network restores CF protein function

August 1, 2012

Researchers at the University of Iowa Carver College of Medicine have discovered a genetic process that can restore function to a defective protein, which is the most common cause of cystic fibrosis (CF).

is an inherited disease caused by mutations in a gene that adversely affect its protein product. In its correct form and cellular location, this protein, cystic fibrosis transmembrane conductance regulator (CFTR), functions as a channel for ions to move across cell membranes, and is critical for maintaining cellular salt and water balance.

The most common CF-causing genetic mutation, known as delta F508, disrupts the process whereby the CFTR protein is folded into its correct shape and shipped to the membranes of cells that line the airways and other organs. Most of the defective CFTR protein is misprocessed and gets degraded. The lack of normal CFTR leads to numerous problems, including and inflammation, the major causes of disease and death in cystic fibrosis.

Despite its importance, how the CFTR protein is made and delivered to cell membranes in its functioning form is not well understood. The UI team led by Paul McCray, M.D., professor of pediatrics and microbiology with UI Health Care and the Roy J. Carver Chair in Pulmonary Research and Vice Chair for Research in Pediatrics, investigated the role of microRNAs -- small non-coding stretches of RNA -- in regulating expression of CFTR.

In their research, McCray and colleagues discovered that one particular microRNA, called miR-138, helps control the biosynthesis of CFTR by regulating a network of genes involved in the production and processing of the protein. The study, published online the week of July 30 in the (PNAS) Early Edition, shows that that miR-138 acts on the other genes to orchestrate a cellular program that increases production of CFTR and increases the amount of the protein that is transported to the cell membrane where it functions as an ion channel.

"We first wanted to determine how this gene network impacts the CFTR protein produced in people who don't have cystic fibrosis," says lead author Shyam Ramachandran, Ph.D.. "We identified a novel regulatory circuit, but then asked ourselves if any of this affected the mutant protein."

Surprisingly, the researchers found that when the gene network was activated by miR-138, it not only increased the amount of the mutated protein, but also partially restored the protein's function.

By manipulating the microRNA network, the UI team was able to change the fate of the misfolded CFTR from being degraded in the cell to functioning as an ion channel in the cell membrane.

"This was a very surprising finding," Ramachandran says. "It unexpectedly helps rescue the function of the mutant protein."

Because most people with CF have one or two copies of the delta F508 mutation, interventions that overcome the CFTR protein-processing problems caused by this mutation might have important implications for new ways of treating CF.

"In the field of CF therapeutics there's great interest in identifying ways to restore the function of this misprocessed ," McCray says. "We were very surprised that manipulating this regulated had this rescuing effect. This opens up a new avenue for the development of CF therapies."

Explore further: An 'unconventional' path to correcting cystic fibrosis

Related Stories

An 'unconventional' path to correcting cystic fibrosis

September 1, 2011
Researchers have identified an unconventional path that may correct the defect underlying cystic fibrosis, according to a report in the September 2nd issue of the journal Cell. This new treatment dramatically extends the ...

New research could provide roadmap for more effective drug discovery for cystic fibrosis

March 12, 2012
A recent study led by Gergely Lukacs, a professor at McGill University's Faculty of Medicine, Department of Physiology, and published in the January issue of Cell, has shown that restoring normal function to the mutant gene ...

Computer-designed molecules point to new therapy for cystic fibrosis

April 19, 2012
By developing software that uses 3-D models of proteins involved in cystic fibrosis, a team of scientists at Duke University has identified several new molecules that may ease the symptoms of the disease.

Unraveling a new regulator of cystic fibrosis

September 19, 2011
Cystic fibrosis (CF), a chronic disease that clogs the lungs and leads to life-threatening lung infections, is caused by a genetic defect in a chloride channel called cystic fibrosis transmembrane conductase regulator (CFTR). ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.