#18 IM

NUR8 – 2019
Cystic Fibrosis: A Disease Associated with Proteins
I. Introduction
Cystic Fibrosis (CF) is a monogenetic disorder generated through alterations in the Cystic
Fibrosis Transmembrane Conductance Regulator (CFTR). The gene responsible for this disease
was first discovered and described almost 30 years ago. This has then led to more information
gathered that would help address the causes of the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) mutations as well as explain the cellular and molecular basis of the disease.
Although this disease affects a lot of the body’s organs, it is most pretentious in the digestive
system and respiratory system, particularly in the lungs where chronic obstructive lung diseases
emerge from. It is also characterized by exocrine pancreatic insufficiency which may result in
gastrointestinal malabsorption, abnormalities in the intestines that may lead to impaired growth,
malnutrition as well as other manifestations that include diabetes and sinusitis.
II. Discussion
Cystic Fibrosis
Cystic Fibrosis is one of the most common fatal genetic diseases among whites
particularly in Caucasians but is also occurring in other ethnic and racial populations. Around
1,000 new cases of Cystic Fibrosis are diagnosed annually. Moreover, 70% of those diagnosed
were from the age of 2 or younger. As years progressed, there has been a higher chance of
survival and Cystic Fibrosis has been dubbed as chronic lung disease from being a disease with
a high infant mortality rate. Among Americans, it was estimated that more than 10 million of them
were carriers of the defective gene without showing any signs and symptoms and have acquired
one copy of the defective gene. Although there are a lot of cases wherein patients who were
positive of Cystic Fibrosis did not show any signs or symptoms of the said disease, there are still
who may have not been diagnosed but may have Cystic Fibrosis. The primary pulmonary
symptoms that can be associated with Cystic Fibrosis are coughing, sputum production or the
thick mucus also known as phlegm, wheezing, chest tightening, difficulty in breathing or shortness
of breath and having a fever. There are also emotional impacts such as frustration, depression or
sadness, worry, difficulty in sleeping, and irritability.
Cystic Fibrosis (CF) still prevails as one of the most common lethal diseases that can be
inherited and is a condition that shortens the life span of a person as it may affect infants as well
as adults. This disease affects many of the body’s organs and systems. It is most common in the
lungs wherein it results in airway surface liquid depletion. Since this is essential in supporting
ciliary stability and functioning, cilia collapse which results in sticky mucus that is not being
transported. Therefore, it clogs the air pathways and consequently, may obstruct the pancreas
and lead to other complications. The mucus produced by Cystic Fibrosis contains limited intact
mucin which binds bacteria and helps in clearing bacteria along the airway. As a result, a shortage
of mucin may increase the risk of the Cystic Fibrosis epithelium to be exposed to bacteria and
hence, trigger inflammation. It also becomes a cycle on infection wherein the most commonly
associated bacterial species with Cystic Fibrosis are the Staphylococcus aureus, Haemophilus
influenzae and the most important is Pseudomonas aeruginosa. Cystic Fibrosis also leads to
phlegm retention thus limiting the ability to breathe.
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
The Cystic Fibrosis Transmembrane Conductance Regulator protein is a multi-domain
membrane protein that is part of the family of adenine triphosphate (ATP) nucleotide-binding
cassette transporters which is composed of two transmembrane domains, two nucleotide-binding
domains (NBDs) and one unique regulatory domain. It is also an epithelial ion channel that
contributes to the regulation of the secretion and absorption of salt and water in different tissues,
as well as in the lungs, pancreas, gastrointestinal tracts and sweat glands. A defect in the Cystic
Fibrosis gene leads to the absence or malfunctioning of the CFTR protein which affects the
quantity of protein that reaches the cell surface. Due to its dysfunction, the defect causes chronic
mucus obstruction, bacterial infections in the Cystic Fibrosis airways and neutrophilic
inflammations. Such inflammations may lead to escalating lung diseases, eventually into
pulmonary failure, which is the main cause of death in Cystic Fibrosis. The missense mutation
G551D is the most common example wherein about 4 to 5% of patients with cystic fibrosis have
this type of mutation on at least one allele.
Throughout the years, more mutations concerning the CFTR protein have been
discovered. Around 1,700 mutations have been described and discovered but many of them are
poorly understood and most of them are rare. Less than 10 mutations concerning Cystic Fibrosis
occur frequently and the most common mutation worldwide is caused by the deletion of
phenylalanine in position 508 or DF508 is detected in approximately 66% of the patients with
Cystic Fibrosis. CFTR mutations can be classified according to their functional consequences:
(Class I) No functional protein was produced, (Class II) process of protein was diminished, (Class
III) Protein was not synthesized, (Class IV) Abnormal or decreased conductance, (Class V)
Protein has partially defective production and lastly, (Class VI) Decreased stability of cell surface.
Classes I to III mutations are more common among the rest and are associated with pancreatic
insufficiency. The other three classes of mutations pertain to pancreatic sufficient.
Therapies
There are no available cures for Cystic Fibrosis, but a lot of therapies are available for this
disease. The principal components of pulmonary care with those who have Cystic Fibrosis are
knowledge, participation, and monitoring of self which will be possible through the cooperation of
the patients and those who are around them.
Pulmonary disease
Therapies such as Mucolytic and hydrator therapies will also help in mucociliary clearance
and improve the lung function as well as reduce exacerbations. Antibiotics particularly those with
P. aeruginosa can use nebulized antibiotics which can help in improving lung function, reduce
exacerbation and increase the weight of the patient. Macrolides, another type of antibiotic may be
used to reduce pulmonary exacerbation rate and can help with anti-inflammatory effects rather
than antibacterial. Anti-inflammatory therapies such as oral corticosteroids, inhaled
corticosteroids and other drugs that respond to inflammation. Lung transplantation can be a
treatment for those patients who are at the end-stage of pulmonary disease.
Treatment of the basic defect
A lot of therapies revolving around the treatment of CFTR dysfunction work through
inserting a normal copy of the protein into the patient’s cells also known as Gene Therapy. It can
also be treated through CFTR pharmacotherapy by opening the probability of existing channels
as well as improving the expression of CFTR on the cell surface. Other therapies and treatments
such as Translational readthrough therapy, CFTR potentiator therapy, and Intracellular trafficking
will help in treating Cystic Fibrosis.
III. References

De Boeck, K. & Amaral, M.D. “Progress in Therapies for Cystic Fibrosis.” The Lancet Respiratory
Medicine, vol. 4, no. 8, Aug. 2016, pp. 662–674,
www.thelancet.com/journals/lanres/article/PIIS2213-2600(16)00023-0/fulltext,
10.1016/s2213-2600(16)00023-0. Accessed 17 Sept. 2019.
Döring, G., Flume, P., Heijerman, H. and Elborn, J.S. (2012). Treatment of lung infection in
patients with cystic fibrosis: Current and future strategies. Journal of Cystic Fibrosis,
[online] 11(6), pp.461–479. Available at:
https://www.sciencedirect.com/science/article/pii/S1569199312001841 [Accessed 17
Aug. 2019].

Flume, Patrick A., et al. “Cystic Fibrosis Pulmonary Guidelines.” American Journal of Respiratory
and Critical Care Medicine, vol. 180, no. 9, Nov. 2009, pp. 802–808,
10.1164/rccm.200812-1845pp. Accessed 17 Sept. 2019.

Goss, C.H., Edwards, T.C., Ramsey, B.W., Aitken, M.L. and Patrick, D.L. (2009). Patient-reported
respiratory symptoms in cystic fibrosis. Journal of Cystic Fibrosis, [online] 8(4), pp.245–
252. Available at: https://www.cysticfibrosisjournal.com/article/S1569-1993(09)00037-
X/fulltext [Accessed 17 Sep. 2019].

LiPuma, J.J. “The Changing Microbial Epidemiology in Cystic Fibrosis.” Clinical Microbiology
Reviews, vol. 23, no. 2, 1 Apr. 2010, pp. 299–323, cmr.asm.org/content/23/2/299.short,
10.1128/cmr.00068-09. Accessed 2 Apr. 2019.

Lomas, P., & Fowler, S. (2010). ORIGINAL RESEARCH: Parents and Children with Cystic
Fibrosis: A Family Affair: Results of a survey and the nursing implications. The American
Journal of Nursing, 110(8), 30-39. Retrieved from http://www.jstor.org/stable/27867444

Mall, M. & Hartl, D. (2014). CFTR: cystic fibrosis and beyond. European Respiratory
Journal, 44(4), 1042-1054. doi: 10.1183/09031936.00228013

Ramsey, B.W., et al. “A CFTR Potentiator in Patients with Cystic Fibrosis and
TheG551DMutation.” New England Journal of Medicine, vol. 365, no. 18, 3 Nov. 2011, pp.
1663–1672, 10.1056/nejmoa1105185.

Ratjen, F.A. et al. “Cystic Fibrosis.” Nature Reviews Disease Primers, vol. 1, 14 May 2015, p.
15010, 10.1038/nrdp.2015.10.

Ratjen, F.A. “Cystic Fibrosis: Pathogenesis and Future Treatment Strategies.” Respiratory Care,
vol. 54, no. 5, May 2009, pp. 595–605, rc.rcjournal.com/content/54/5/595/tab-pdf.
Accessed 17 Sept. 2019.