Cystic Fibrosis (CF)

Cystic fibrosis (CF) is the most common life-shortening illness among whites in the United States. Among people of northern European descent, the annual incidence of CF is 1 in 3500. Although CF is a multiorgan disease, morbidity and mortality in persons with CF are caused primarily by pulmonary problems.1 The inheritance of CF is autosomal recessive.The disease was previously incurable and fatal in children, but now a majority of patients live to adulthood.2 CF is caused by mutations in the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR).3 The identification of the CFTR gene has changed the lives of persons with CF by making it possible for them to receive therapy that, if given in early childhood years, can avert serious consequences.2 

Characteristics of the Human Cystic Fibrosis Gene and Encoded CFTR Protein

The structure of normal CFTR protein comprises 2 groups of 6 membrane-spanning structural motifs, 2 intracellular nucleotide-binding folds (NBFs), and a highly charged “R domain,” including several phosphorylation sites. Phosphokinase A-mediated phosphorylation of the R domain and sustained adenosine triphosphate (ATP) levels within the NBFs are required for chloride channel activation.3 

The CFTR gene is located on the long arm of chromosome 7. The CFTR protein is found predominantly in the apical membranes of secretory epithelia (which secrete mucus, sweat, and digestive juices) in a number of organs, including the sweat glands, lungs, pancreas, and intestine. CFTR is primarily an anion channel that also functions as a bicarbonate channel and a cyclic adenosine monophosphate (cAMP)-dependent chloride channel. CFTR helps to transport chloride and bicarbonate across secretory epithelia, regulating salt and water secretion and absorption as well as epithelial surface hydration.4 

CFTR mutations disrupt the expression, function, and stability of messenger RNA (mRNA) and CFTR protein, interfering with fluid and electrolyte homeostasis. One of the main signs of CF is an aberrant excessive release of salt from the sweat glands that is not reabsorbed by the sweat duct cells. The gold standard for diagnosing CF is measurement of the chloride excreted in sweat.4 

Genetic Mutation Types in CFTR

Approximately 2000 distinct mutations that have been identified in the CFTR gene may cause illness.5 The mutations have been divided into 6 different classes, each corresponding to a specific type of CFTR dysfunction. The mutations of classes I through III generally induce more severe disease than the mutations of classes IV through VI.3

The most common mutation is delta F508, which affects 70% of white patients with CF in the United States and two-thirds of all affected individuals globally. This is a class II mutation that causes aberrant folding of the CFTR protein; as a result, the protein is destroyed prematurely within the Golgi apparatus. Exocrine pancreatic insufficiency and an increased risk for meconium ileus are common effects of the delta F508 mutation.5 

Class I Mutations: Defective Protein Production 

As a result of nonsense, frameshift, or splice-site mutations, mRNA transcripts are prematurely terminated, and the CFTR protein is completely absent. G542X, W1282X, R553X, 621+G>T, and 1717-1G>A are some examples.3 

Class II Mutations: Defective Protein Processing 

The F508del mutation is an example of a class II mutation. Nearly 50% of patients with CF are homozygous and at least 90% of those with CF are heterozygous for this mutation. Class II mutations cause abnormal post-translational processing of the CFTR protein, preventing trafficking of the protein to the correct cellular location.3 

Class III Mutations: Defective Regulation 

Even when ATP levels are sufficient, class III mutations are associated with decreased channel activation. Many mutations affect the NBF ATP-binding areas (named NBO1 and NBO2), resulting in various degrees of nucleotide-binding sensitivity. In Caucasian populations, the mutation that causes the CFTR protein amino acid substitution G551D, which prevents ATP binding, is the most common class III mutation.3

Class IV Mutations: Defective Conduction 

The CFTR protein is appropriately synthesized and delivered to the cell surface. Despite the fact that chloride currents are created in response to cAMP stimulation, the rate of ion flow and the duration of channel opening are reduced in comparison with the rates in normal CFTR protein. The most prevalent class IV mutation in Caucasian populations causes the CFTR protein amino acid substitution R117H.3 

Class V Mutations: Reduced Amounts of Functional CFTR Protein 

Some classification schemes do not include this category. Class V includes many mutations that affect the stability of mRNA and of mature CFTR protein.3 

Class VI Mutations: Decreased CFTR Stability 

Phe508del is a class VI mutation. It causes significant plasma membrane instability.3 

All mutations result in reduced chloride secretion and, as a consequence, increased salt reabsorption into the cellular space. Higher rates of sodium reabsorption increase water reabsorption, so that the mucus discharged onto epithelial linings is thick and exocrine secretions are viscous. Mucus plugging in obstructive disorders is a result of the secretion of thickened mucus in almost every organ system involved. The sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands are the organs most frequently affected.5  

Credit: Shutterstock

Inheritance Pattern of Cystic Fibrosis

CF is an autosomal-recessive disease. For an individual to have CF, both copies of the CFTR gene in each cell must be mutated. If each parent is a carrier (with 1 mutant and 1 normal gene) and a child inherits a mutant gene from each parent, the child will have CF. The carrier of a disorder with autosomal-recessive transmission shows no signs or symptoms. When 2 carriers of an autosomal-recessive disease have children, each child has a 25% (1 in 4) probability of having CF; a 50% (1 in 2) probability of being a CF carrier, like both parents; and a 25% probability of not having CF and not being a carrier. When 1 parent is a carrier and the other has CF, each child has a 50% (1 in 2) risk of having CF and a 50% (1 in 2) chance of being a CF carrier.


  1. Brown SD, White R, Tobin P. Keep them breathing: cystic fibrosis pathophysiology, diagnosis, and treatment. JAAPA. 2017;30(5):23-27. doi:10.1097/01.JAA.0000515540.36581.92
  2. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr. 2020;109(5):893-899. doi:10.1111/apa.15155
  3. Chen Q, Shen Y, Zheng J. A review of cystic fibrosis: basic and clinical aspects. Animal Model Exp Med. 2021;4(3):220-232. doi:10.1002/ame2.12180
  4. De Palma FDE, Raia V, Kroemer G, Maiuri MC. The multifaceted roles of microRNAs in cystic fibrosis. Diagnostics (Basel). 2020;10(12):1102. doi:10.3390/diagnostics10121102
  5. Yu E, Sharma S. Cystic fibrosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021.
  6. Cystic fibrosis. Genetic and Rare Diseases Information Center (GARD). Updated September 22, 2017. Accessed January 10, 2021. 

Reviewed by Hasan Avcu, MD, on 1/22/2022.