Breathing New Life into Cystic Fibrosis Genetic Testing

July 4, 2016
Breathing New Life into Cystic Fibrosis Genetic Testing
Source: wildpixel / Getty Images

Jeffrey S. Buguliskis, Ph.D.

Imagine yourself suspended a couple of hundred feet below the surface of the ocean. The sheer weight of the immense column of water pushing down on your chest makes each breath a harrowing task. Now picture that your only recourse to collect vital oxygen is to breathe laboriously throw a narrow straw that connects you to the atmosphere above. You slowly draw in air, cautiously trying not to collapse the straw from too forceful of suction—struggling just as much to exhale the expired air. Now repeat the entire cycle for the rest of your life. 

If you were able to envision how the immense difficulties of breathing in this manner would be for just a few minutes, let alone your entire life, then you may have a minute sense of what a person afflicted with cystic fibrosis (CF) endures. Gasping for air while thick, sticky mucus lines the pulmonary system, seemingly threatening to drown and suffocate patients with each inhale.

CF is the most common autosomal recessive life-limiting disease, with a high occurrence among peoples of northwestern European descent and an incidence rate of approximately 1 in every 2,500 individuals. CF arises due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a transmembrane ion channel protein that is a member of the ABC transporter-class—conducting chloride (Cl-) and thiocyanate (SCN-) ions across epithelial cell membranes.

While chronic respiratory issues represent the vast majority of morbidity and mortality associated with CF, the disease often encompasses multiple symptoms with pancreatic insufficiency manifesting in 85 percent of patients and fat malabsorption in 90 percent of infants by one year of age. Many consequences of CFTR abnormalities begin even before birth, leading to incomplete embryo formation and structural changes, causing infertility in virtually all males with CF.

Almost 2,000 mutations have been discovered for the CFTR gene resulting in varying degrees of disease severity. Mutations in CFTR are often classified into six, non-exclusive categories based on the cellular mechanisms that are affected. They can run the gamut of large frameshift and RNA splicing mutations, resulting in reduced protein expression and transport, to single base errors, which often lead to gating and conductance issues.  

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