Cystic fibrosis transmembrane conductance regulator explained

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.^{[1] [2]}

Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with CF (cystic fibrosis).^[3]

The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride^[4] and bicarbonate ions across epithelial cell membranes. Mutations of the CFTR gene affecting anion channel function lead to dysregulation of epithelial lining fluid (mucus) transport in the lung, pancreas and other organs, resulting in cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes.^[5] These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing vas deferens (spermatic cord) and epididymis appear to result from abnormal intraluminal secretions,^[6] causing congenital absence of the vas deferens and male infertility, and found associated with an imbalance of fatty acids.^[7]

Gene

The gene that encodes the human CFTR protein is found on chromosome 7, on the long arm at position q31.2. from base pair 116,907,253 to base pair 117,095,955. CFTR orthologs^[8] occur in the jawed vertebrates.^[9]

Each individual inherits two copies of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. However, some of the inherited copies have been altered. So far, the CFTR gene has been associated with over 700 distinct mutations. An individual with CF inherits two defective copies of the CFTR gene. These mutations might be heterozygous, meaning they include two different mutations, and homozygous, meaning they involve the same mutation.^[10] Delta F508 is the most common mutation, accounting for more than 70% of all mutations. Those who are homozygous for Delta F508 are commonly affected by pancreatic insufficiency.^[11]

The CFTR gene has been used in animals as a nuclear DNA phylogenetic marker. Large genomic sequences of this gene have been used to explore the phylogeny of the major groups of mammals,^[12] and confirmed the grouping of placental orders into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.

Mutations

Nearly 1000 cystic fibrosis-causing mutations have been described.^[13] The most common mutation, DeltaF508 (ΔF508) primarily known as a processing mutation which results from a deletion (Δ) of three nucleotides which results in a loss of the amino acid phenylalanine (F) at the 508th position on the protein.^[14] As a result, the protein does not fold normally and is more quickly degraded. The vast majority of mutations are infrequent. The distribution and frequency of mutations varies among different populations which has implications for genetic screening and counseling.

Drug discovery for therapeutics to address CF in all patients is complicated due to a large number of disease-causing mutations. Ideally, a library of cell lines and cell-based assays corresponding to all mutants is required to screen for broadly-active drug candidates. Cell engineering methods including fluorogenic oligonucleotide signaling probes may be used to detect and isolate clonal cell lines for each mutant.^[15]

Mutations consist of replacements, duplications, deletions or shortenings in the CFTR gene. This may result in proteins that may not function, work less effectively, are more quickly degraded, or are present in inadequate numbers.^[16]

It has been hypothesized that mutations in the CFTR gene may confer a selective advantage to heterozygous individuals. Cells expressing a mutant form of the CFTR protein are resistant to invasion by the Salmonella typhi bacterium, the agent of typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin.^[17]

The most common mutations that cause cystic fibrosis and pancreatic insufficiency in humans are:^[18]

Variant cDNA name (ordered 5' to 3')	Variant protein name	Variant legacy name	rsID	alleles in CFTR2	Allele frequency in CFTR2	% pancreatic insufficient	Variant final determination (July 2020)
c.1521_1523delCTT	p.Phe508del	F508del	rs113993960	99061	0.69744	98%	CF-causing
c.1624G>T	p.Gly542X	G542X	rs113993959	3610	0.02542	98%	CF-causing
c.1652G>A	p.Gly551Asp	G551D	rs75527207	2986	0.02102	96%	CF-causing
c.3909C>G	p.Asn1303Lys	N1303K	rs80034486	2246	0.01581	98%	CF-causing
c.350G>A	p.Arg117His	R117H	rs78655421	1854	0.01305	23%	Varying clinical consequence
c.3846G>A	p.Trp1282X	W1282X	rs77010898	1726	0.01215	99%	CF-causing
c.489+1G>T	No protein name	621+1G->T	rs78756941	1323	0.00931	99%	CF-causing
c.1657C>T	p.Arg553X	R553X	rs74597325	1323	0.00931	97%	CF-causing
c.1585-1G>A	No protein name	1717-1G->A	rs76713772	1216	0.00856	97%	CF-causing
c.3718-2477C>T	No protein name	3849+10kbC->T	rs75039782	1158	0.00815	33%	CF-causing
c.2657+5G>A	No protein name	2789+5G->A	rs80224560	1027	0.00723	43%	CF-causing
c.1519_1521delATC	p. Ile507del	I507del	rs121908745	651	0.00458	98%	CF-causing
c.3484C>T	p.Arg1162X	R1162X	rs74767530	651	0.00458	97%	CF-causing
c.254G>A	p.Gly85Glu	G85E	rs75961395	616	0.00434	85%	CF-causing
c.3454G>C	p.Asp1152His	D1152H	rs75541969	571	0.00402	24%	Varying clinical consequence
c.2051_2052delAAinsG	p. Lys684SerfsX38	2183AA->G	rs121908799	542	0.00382	96%	CF-causing
c.3528delC	p. Lys1177SerfsX15	3659delC	rs121908747	539	0.00379	99%	CF-causing
c.1040G>C	p.Arg347Pro	R347P	rs77932196	533	0.00375	68%	CF-causing
c.1210−12T[5]	No protein name	5T	rs1805177	516	0.00363	28%	Varying clinical consequence
c.2988+1G>A	No protein name	3120+1G->A	rs75096551	501	0.00353	98%	CF-causing
c.1364C>A	p.Ala455Glu	A455E	rs74551128	500	0.00352	34%	CF-causing
c.3140-26A>G	No protein name	3272-26A->G	rs76151804	470	0.00331	29%	CF-causing
c.1000C>T	p.Arg334Trp	R334W	rs121909011	429	0.00302	40%	CF-causing
c.1766+1G>A	No protein name	1898+1G->A	rs121908748	421	0.00296	99%	CF-causing
c.54-5940_273+10250del21kb	p.Ser18ArgfsX16	CFTRdele2,3	not found	417	0.00294	100%	CF-causing
c.1679G>C	p.Arg560Thr	R560T	rs80055610	343	0.00241	98%	CF-causing
c.617T>G	p. Leu206Trp	L206W	rs121908752	333	0.00234	20%	CF-causing
c.2052dupA	p.Gln685ThrfsX4	2184insA	rs121908786	329	0.00232	85%	CF-causing
c.262_263delTT	p. Leu88IlefsX22	394delTT	rs121908769	307	0.00216	97%	CF-causing
c.178G>T	p.Glu60X	E60X	rs77284892	296	0.00208	99%	CF-causing
c.1477C>T	p.Gln493X	Q493X	rs77101217	292	0.00206	98%	CF-causing
c.579+1G>T	No protein name	711+1G->T	rs77188391	274	0.00193	98%	CF-causing
c.2052delA	p. Lys684AsnfsX38	2184delA	rs121908746	255	0.00180	98%	CF-causing
c.200C>T	p.Pro67Leu	P67L	rs368505753	239	0.00168	34%	CF-causing
c.3302T>A	p.Met1101Lys	M1101K	rs36210737	238	0.00168	69%	CF-causing
c.1408A>G	p.Met470Val	M470V	rs213950	235	0.00165	46%	Non CF-causing
c.3276C>A or c.3276C>G	p.Tyr1092X	Y1092X	rs121908761	225	0.00158	98%	CF-causing
c.3196C>T	p.Arg1066Cys	R1066C	rs78194216	220	0.00155	98%	CF-causing
c.1021_1022dupTC	p.Phe342HisfsX28	1154insTC	rs387906360	214	0.00151	99%	CF-causing
c.3773dupT	p. Leu1258PhefsX7	3905insT	rs121908789	210	0.00148	97%	CF-causing
c.1646G>A	p.Ser549Asn	S549N	rs121908755	203	0.00143	84%	CF-causing
c.1040G>A	p.Arg347His	R347H	rs77932196	199	0.00140	24%	CF-causing
c.948delT	p.Phe316LeufsX12	1078delT	rs121908744	184	0.00130	99%	CF-causing
c.1210-33_1210-6GT[12]T[4]	No protein name	5T;TG12	not found	182	0.00128	14%	Varying clinical consequence
c.3472C>T	p.Arg1158X	R1158X	rs79850223	179	0.00126	99%	CF-causing
c.2834C>T	p.Ser945Leu	S945L	rs397508442	167	0.00118	40%	CF-causing
c.1558G>T	p. Val520Phe	V520F	rs77646904	156	0.00110	98%	CF-causing
c.443T>C	p. Ile148Thr	I148T	rs35516286	148	0.00104	88%	Non CF-causing
c.349C>T	p.Arg117Cys	R117C	rs77834169	146	0.00103	24%	CF-causing

DeltaF508

DeltaF508 (ΔF508), full name CFTRΔF508 or F508del-CFTR (rs113993960), is a specific mutation within the CFTR gene involving deletion of three nucleotides spanning codons for amino acid positions 507 and 508 of the CFTR gene on chromosome 7, which ultimately results in the loss of a single codon for the amino acid phenylalanine (F). A person with the CFTRΔF508 mutation will produce an abnormal CFTR protein that lacks this phenylalanine residue and which cannot fold properly. Most of this mutated protein does not escape the endoplasmic reticulum for further processing. The small amounts that reach the plasma membrane are destabilized and the anion channel opens infrequently. Having two copies of this mutation (one inherited from each parent) is by far the most common cause of cystic fibrosis (CF), responsible for nearly two-thirds of mutations worldwide.^[19]

Effects

The CFTR protein is largely expressed in cells of the pancreas, intestinal and respiratory epithelia, and all exocrine glands. When properly folded, it is shuttled to the cell membrane, where it becomes a transmembrane protein that forms aqueous channels allowing the flow of chloride and bicarbonate ions out of cells; it also simultaneously inhibits the uptake of sodium ions by another channel protein. Both of these functions help to maintain an ion gradient that causes osmosis to draw water out of the cells.^[20] The ΔF508 mutation leads to the misfolding of CFTR and its eventual degradation in the ER. In organisms with two complements of the mutation, the protein is almost entirely absent from the cell membrane, and these critical ion transport functions are not performed.^[21]

Having a homozygous pair of genes with the ΔF508 mutation prevents the CFTR protein from assuming its normal position in the cell membrane. This causes increased water retention in cells, corresponding dehydration of the extracellular space, and an associated cascade of effects on various parts of the body. These effects include: thicker mucous membranes in the epithelia of afflicted organs; obstruction of narrow respiratory airways as a result of thicker mucous and inhibition of the free movement of muco cilia; congenital absence of the vas deferens due to increased mucus thickness during fetal development; pancreatic insufficiency due to blockage of the pancreatic duct with mucus; and increased risk of respiratory infection due to build-up of thick, nutrient-rich mucus where bacteria thrive. These are the symptoms of cystic fibrosis, a genetic disorder; however, ΔF508 is not the only mutation that causes this disorder.^[22]

Being a heterozygous carrier (having a single copy of ΔF508) results in decreased water loss during diarrhea because malfunctioning or absent CFTR proteins cannot maintain stable ion gradients across cell membranes. Typical nucleotide-binding-up of both Cl⁻ and Na⁺ ions inside affected cells, creating a hypotonic solution outside the cells and causing water to diffuse into the cells by osmosis. Several studies indicate that heterozygous carriers are at increased risk for various symptoms. For example, it has been shown that heterozygosity for cystic fibrosis is associated with increased airway reactivity, and heterozygotes may be at risk for poor pulmonary function. Heterozygotes with wheeze have been shown to be at higher risk for poor pulmonary function or development and progression of chronic obstructive lung disease. One gene for cystic fibrosis is sufficient to produce mild lung abnormalities even in the absence of infection.^[23]

Mechanism

The CFTR gene is located on the long arm of chromosome 7, at position q31.2, and ultimately codes for a sequence of 1,480 amino acids. Normally, the three DNA base pairs A-T-C (paired with T-A-G on the opposite strand) at the gene's 507th position form the template for the mRNA codon A-U-C for isoleucine, while the three DNA base pairs T-T-T (paired with A-A-A) at the adjacent 508th position form the template for the codon U-U-U for phenylalanine.^[24] The ΔF508 mutation is a deletion of the C-G pair from position 507 along with the first two T-A pairs from position 508, leaving the DNA sequence A-T-T (paired with T-A-A) at position 507, which is transcribed into the mRNA codon A-U-U. Since A-U-U also codes for isoleucine, position 507's amino acid does not change, and the mutation's net effect is equivalent to a deletion ("Δ") of the sequence resulting in the codon for phenylalanine at position 508.^[25]

Prevalence

ΔF508 is present on at least one copy of chromosome 7 in approximately one in 30 Caucasians. Presence of the mutation on both copies causes the autosomal recessive disease cystic fibrosis. Scientists have estimated that the original mutation occurred over 52,000 years ago in Northern Europe though cystic fibrosis patients of other ethnicities are also known to harbor the mutation. The young allele age may be a consequence of past selection. One hypothesis as to why the otherwise detrimental mutation has been maintained by natural selection is that a single copy may present a positive effect by reducing water loss during cholera, though the introduction of pathogenic Vibrio cholerae into Europe did not occur until the late 18th century.^[26] Another theory posits that CF carriers (heterozygotes for ΔF508) are more resistant to typhoid fever, since CFTR has been shown to act as a receptor for Salmonella typhi bacteria to enter intestinal epithelial cells.^[27]

Cystic fibrosis ΔF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than non-carriers.^{[28] [29]} Carriers of a single CF mutation have a higher prevalence of chronic rhinosinusitis than the general population.^[30] Approximately 50% of cystic fibrosis cases in Europe are due to homozygous ΔF508 mutations (this varies widely by region),^[31] while the allele frequency of ΔF508 is about 70%.^[32] The remaining cases are caused by over 1,500 other mutations, including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or even a single copy of ΔF508, may cause CF symptoms. The genotype is not strongly correlated with severity of the CF, though specific symptoms have been linked to certain mutations.

Structure

The CFTR gene is approximately 189 kb in length, with 27 exons and 26 introns.^[33] CFTR is a glycoprotein and is found on the surface of many epithelial cells in the body.^[34] CFTR consists of 5 domains, which include 2 transmembrane or membrane-spanning domains, 2 nucleotide-binding domains and a regulatory domain.^[35] The transmembrane domains are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters which carries 19 predicted sites for protein kinase A(PKA). Six of these have been reported to be phosphorylated in vivo.^[36] The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs. Phosphorylation displaces the disordered R domain from positions preventing NBD dimerization and opening.^{[37] [38]} The amino-terminus is part of the lasso motif which anchors into the cell membrane.^[36] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.^[39] The structure is shas(PDBitsI) shows a homopentameric assembly of mutated NBD1, the first nucleotide binding domain (NBD1) of the transporter

Location and function

The CFTR gene is made up of 27 exons that encode its gene makeup and is found on the long (q) arm of chromosome 7 at locus 31.2. Exons are DNA fragments that provide the code for a protein structure.^[34] CFTR functions as phosphorylation and ATP-gated anion channel, increasing the conductance for certain anions (e.g. Cl⁻) to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow the transmembrane flow of anions down their electrochemical gradient.^[1] This in contrast to other ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes. Essentially, CFTR is an ion channel that evolved as a 'broken' ABC transporter that leaks when in the open conformation.

CFTRs consist of five domains including two trans-membrane domains, each linked to a nucleotide-binding domain. CFTR also contains another domain called the regulatory domain. Other members of the ABC transporter superfamily are involved in the uptake of nutrients in prokaryotes, or in the export of a variety of substrates in eukaryotes. ABC transporters have evolved to transduce the free energy of ATP hydrolysis to the uphill movement of substrates across the cell membrane. They have two main conformations, one where the cargo binding site is facing the cytosol or inward facing (ATP free), and one where it is outward facing (ATP bound). ATP binds to each nucleotide-binding domain, which results in the subsequent NBD dimerization, leading to the rearrangement of the transmembrane helices. This changes the accessibility of the cargo binding site from an inward-facing position to an outward facing one. ATP binding, and the hydrolysis that follows, drives the alternative exposure of the cargo binding site, ensuring a unidirectional transport of cargo against an electrochemical gradient. In CFTR, alternating between an inward-facing conformation to an outward-facing one results in channel gating. In particular, NBD dimerization (favored by ATP binding) is coupled to transition to an outward-facing conformation in which an open transmembrane pathway for anions is formed.^[40] Subsequent hydrolysis (at the canonical active site, site 2, including Walker motifs of NBD2) destabilizes the NBD dimer and favors return to the inward-facing conformation, in which the anion permeation pathway is closed off.^[1]

The CFTR is found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, and the female^[41] and male reproductive tracts.^{[42] [43]}

In the airways of the lung, CFTR is most highly expressed by rare specialized cells called pulmonary ionocytes.^{[44] [45] [46]} In the skin, CFTR is strongly expressed in the sebaceous and eccrine sweat glands.^[47] In the eccrine glands, CFTR is located on the apical membrane of the epithelial cells that make up the duct of these sweat glands.

Normally, the protein allows movement of chloride, bicarbonate and thiocyanate^[48] ions (with a negative charge) out of an epithelial cell into the Airway Surface Liquid and mucus. Positively charged sodium ions follow passively, increasing the total electrolyte concentration in the mucus, resulting in the movement of water out of the cell via osmosis.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on the apical cell membrane but not on cilia. In contrast, ENaC (Epithelial sodium channel) is located along the entire length of the cilia.

In sweat glands, defective CFTR results in reduced transport of sodium chloride and sodium thiocyanate^[49] in the resorptive duct and therefore saltier sweat. This is the basis of a clinically important sweat test for cystic fibrosis often used diagnostically with genetic screening.^[50]

Clinical Implications

Different CFTR mutations can lead to varying degrees of cystic fibrosis severity. Common symptoms include chronic lung infections, pancreatic insufficiency, and high sweat chloride levels. Mutation-specific therapies, such as CFTR modulators, have been developed to address these specific genetic defects.^[51]

Interactions

Cystic fibrosis transmembrane conductance regulator has been shown to interact with:

• DNAJC5,^[52]
• GOPC,^{[53] [54]}
• PDZK1,^{[54] [55]}
• PRKCE,^[56]
• SLC4A8,
• SNAP23,^[57]
• SLC9A3R1,^{[39] [58] [59] [60] [61] [62]}
• SLC9A3R2,^[63] and
• STX1A,^{[57] [64]}

It is inhibited by the anti-diarrhoea drug crofelemer.

Related conditions

• Congenital bilateral absence of vas deferens: Males with congenital bilateral absence of the vas deferens most often have a mild mutation (a change that allows partial function of the gene) in one copy of the CFTR gene and a cystic fibrosis-causing mutation in the other copy of CFTR.
• Cystic fibrosis: More than 1,800 mutations in the CFTR gene have been found^[65] but the majority of these have not been associated with cystic fibrosis.^[66] Most of these mutations either substitute one amino acid (a building block of proteins) for another amino acid in the CFTR protein or delete a small amount of DNA in the CFTR gene. The most common mutation, called ΔF508, is a deletion (Δ) of one amino acid (phenylalanine) at position 508 in the CFTR protein. This altered protein never reaches the cell membrane because it is degraded shortly after it is made. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed by cilia; thick mucus cannot, so it traps bacteria that give rise to chronic infections.
• Cholera: ADP-ribosylation caused by cholera toxin results in increased production of cyclic AMP which in turn opens the CFTR channel which leads to Over secretion of Cl⁻. Na⁺ and H₂O follow Cl⁻ into the small intestine, resulting in dehydration and loss of electrolytes.^[67]

Drug target

CFTR has been a drug target in efforts to find treatments for related conditions. Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved by the FDA in 2012 for people with cystic fibrosis who have specific CFTR mutations.^{[68] [69]} Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.^[70] Called "the most important new drug of 2012",^[71] and "a wonder drug"^[72] it is one of the most expensive drugs, costing over per year, which has led to criticism of Vertex for the high cost.

Further reading

• Kulczycki LL, Kostuch M, Bellanti JA . A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations . American Journal of Medical Genetics. Part A . 116A . 3 . 262–267 . January 2003 . 12503104 . 10.1002/ajmg.a.10886 . 9245855 .
• Vankeerberghen A, Cuppens H, Cassiman JJ . The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions . Journal of Cystic Fibrosis . 1 . 1 . 13–29 . March 2002 . 15463806 . 10.1016/S1569-1993(01)00003-0 . free .
• Tsui LC . Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium . Human Mutation . 1 . 3 . 197–203 . 1992 . 1284534 . 10.1002/humu.1380010304 . 35904538 . free .
• McIntosh I, Cutting GR . Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis . FASEB Journal . 6 . 10 . 2775–2782 . July 1992 . 1378801 . 10.1096/fasebj.6.10.1378801 . free . 24932803 .
• Drumm ML, Collins FS . Molecular biology of cystic fibrosis . Molecular Genetic Medicine . 3 . 33–68 . 1993 . 7693108 . 10.1016/b978-0-12-462003-2.50006-7 . 9780124620032 .
• Kerem B, Kerem E . The molecular basis for disease variability in cystic fibrosis . European Journal of Human Genetics . 4 . 2 . 65–73 . 1996 . 8744024 . 10.1159/000472174 . 41476164 .
• Devidas S, Guggino WB . CFTR: domains, structure, and function . Journal of Bioenergetics and Biomembranes . 29 . 5 . 443–451 . October 1997 . 9511929 . 10.1023/A:1022430906284 . 6000695 .
• Nagel G . Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1461 . 2 . 263–274 . December 1999 . 10581360 . 10.1016/S0005-2736(99)00162-5 . free .
• Boyle MP . Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR? . Respiratory Research . 1 . 3 . 133–135 . 2000 . 11667976 . 59552 . 10.1186/rr23 . free .
• Greger R, Schreiber R, Mall M, Wissner A, Hopf A, Briel M, Bleich M, Warth R, Kunzelmann K . Cystic fibrosis and CFTR . Pflügers Archiv . 443 . S3–S7 . 2001 . Suppl 1 . 11845294 . 10.1007/s004240100635 . 8057614 .
• Bradbury NA . cAMP signaling cascades and CFTR: is there more to learn? . Pflügers Archiv . 443 . S85–S91 . 2001 . Suppl 1 . 11845310 . 10.1007/s004240100651 . 19373036 .
• Dahan D, Evagelidis A, Hanrahan JW, Hinkson DA, Jia Y, Luo J, Zhu T . Regulation of the CFTR channel by phosphorylation . Pflügers Archiv . 443 . S92–S96 . 2001 . Suppl 1 . 11845311 . 10.1007/s004240100652 . 8144727 .
• Cohn JA, Noone PG, Jowell PS . Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene . Journal of Investigative Medicine . 50 . 5 . 247S–255S . September 2002 . 12227654 . 10.1136/jim-50-suppl5-01 . 34017638 .
• Schwartz M . [Cystic fibrosis transmembrane conductance regulator (CFTR) gene: mutations and clinical phenotypes] . Ugeskrift for Laeger . 165 . 9 . 912–916 . February 2003 . 12661515 .
• Wong LJ, Alper OM, Wang BT, Lee MH, Lo SY . Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations . American Journal of Medical Genetics. Part A . 120A . 2 . 296–298 . July 2003 . 12833420 . 10.1002/ajmg.a.20039 . 41060230 .
• Cuppens H, Cassiman JJ . CFTR mutations and polymorphisms in male infertility . International Journal of Andrology . 27 . 5 . 251–256 . October 2004 . 15379964 . 10.1111/j.1365-2605.2004.00485.x . free .
• Cohn JA, Mitchell RM, Jowell PS . The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis . Clinics in Laboratory Medicine . 25 . 1 . 79–100 . March 2005 . 15749233 . 10.1016/j.cll.2004.12.007 .
• Southern KW, Peckham D . Establishing a diagnosis of cystic fibrosis . Chronic Respiratory Disease . 1 . 4 . 205–210 . 2004 . 16281647 . 10.1191/1479972304cd044rs . free .
• Kandula L, Whitcomb DC, Lowe ME . Genetic issues in pediatric pancreatitis . Current Gastroenterology Reports . 8 . 3 . 248–253 . June 2006 . 16764792 . 10.1007/s11894-006-0083-8 . 23606613 .
• Marcet B, Boeynaems JM . Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis . Pharmacology & Therapeutics . 112 . 3 . 719–732 . December 2006 . 16828872 . 10.1016/j.pharmthera.2006.05.010 .
• Wilschanski M, Durie PR . Patterns of GI disease in adulthood associated with mutations in the CFTR gene . Gut . 56 . 8 . 1153–1163 . August 2007 . 17446304 . 1955522 . 10.1136/gut.2004.062786 .

External links

• GeneReviews/NCBI/NIH/UW entry on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD)
• The Cystic Fibrosis Transmembrane Conductance Regulator Protein
• The Human Gene Mutation Database - CFTR Records
• Cystic Fibrosis Mutation Database
• Oak Ridge National Laboratory CFTR Information
• CFTR at OMIM (National Center for Biotechnology Information)

Notes and References

1. Csanády L, Vergani P, Gadsby DC . Structure, Gating, and Regulation of the CFTR Anion Channel . Physiological Reviews . 99 . 1 . 707–738 . January 2019 . 30516439 . 10.1152/physrev.00007.2018 . 32 . free .
2. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N . Identification of the cystic fibrosis gene: chromosome walking and jumping . Science . 245 . 4922 . 1059–1065 . September 1989 . 2772657 . 10.1126/science.2772657 . 1989Sci...245.1059R . Francis Collins .
3. Web site: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene The Embryo Project Encyclopedia . 2022-09-26 . embryo.asu.edu.
4. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA . Science . 245 . 4922 . 1066–1073 . September 1989 . 2475911 . 10.1126/science.2475911 . 84566748 . 1989Sci...245.1066R .
5. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA . Science . 245 . 4922 . 1066–1073 . September 1989 . 2475911 . 10.1016/0168-9525(89)90155-8 .
6. Marcorelles P, Gillet D, Friocourt G, Ledé F, Samaison L, Huguen G, Ferec C . Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development . Human Pathology . 43 . 3 . 390–397 . March 2012 . 21840567 . 10.1016/j.humpath.2011.04.031 .
7. Bregman T, Fride E . Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice . Journal of Basic and Clinical Physiology and Pharmacology . 22 . 1-2 . 29–32 . June 2011 . 22865360 . 10.1515/jbcpp.2011.004 . 19335113 .
8. Web site: OrthoMaM phylogenetic marker: CFTR coding sequence . dead . https://web.archive.org/web/20160302164823/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000001626_CFTR.xml . 2016-03-02 . 2010-03-12.
9. Davies R, Conroy SJ, Davies WL, Potter IC, Trezise AE . 19–23 June 2005 . Evolution and Regulation of the Cystic Fibrosis Gene . conference paper . Molecular Biology and Evolution (MBE05) Conference . 28 July 2014.
10. Welsh MJ, Smith AE . Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis . Cell . 73 . 7 . 1251–1254 . July 1993 . 7686820 . 10.1016/0092-8674(93)90353-r .
11. Web site: Genetics and CF . 2022-10-23 . The Cystic Fibrosis Center at Stanford . sm.
12. Prasad AB, Allard MW, Green ED . Confirming the phylogeny of mammals by use of large comparative sequence data sets . Molecular Biology and Evolution . 25 . 9 . 1795–1808 . September 2008 . 18453548 . 2515873 . 10.1093/molbev/msn104 .
13. Web site: The Clinical and Functional TRanslation of CFTR (CFTR2): CFTR2 Variant List History. US CF Foundation, Johns Hopkins University, Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. 2 August 2017.
14. Guimbellot J, Sharma J, Rowe SM . Toward inclusive therapy with CFTR modulators: Progress and challenges . Pediatric Pulmonology . 52 . S48 . S4–S14 . November 2017 . 28881097 . 6208153 . 10.1002/ppul.23773 .
15. Shekdar K, Langer J, Venkatachalan S, Schmid L, Anobile J, Shah P, Lancaster A, Babich O, Dedova O, Sawchuk D . Cell engineering method using fluorogenic oligonucleotide signaling probes and flow cytometry . Biotechnology Letters . 43 . 5 . 949–958 . May 2021 . 33683511 . 7937778 . 10.1007/s10529-021-03101-5 .
16. Rowe SM, Miller S, Sorscher EJ . Cystic fibrosis . The New England Journal of Medicine . 352 . 19 . 1992–2001 . May 2005 . 15888700 . 10.1056/NEJMra043184 .
17. Kavic SM, Frehm EJ, Segal AS . Case studies in cholera: lessons in medical history and science . The Yale Journal of Biology and Medicine . 72 . 6 . 393–408 . 1999 . 11138935 . 2579035 .
18. Web site: CFTR2 . 2021-07-08.
19. Bobadilla JL, Macek M, Fine JP, Farrell PM . Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening . Human Mutation . 19 . 6 . 575–606 . June 2002 . 12007216 . 10.1002/humu.10041 . free .
20. Verkman AS, Song Y, Thiagarajah JR . Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease . American Journal of Physiology. Cell Physiology . 284 . 1 . C2-15 . January 2003 . 12475759 . 10.1152/ajpcell.00417.2002 .
21. Web site: Cystic Fibrosis Research Directions. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
22. Boyle MP, De Boeck K . A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect . The Lancet. Respiratory Medicine . 1 . 2 . 158–163 . April 2013 . 24429096 . 10.1016/s2213-2600(12)70057-7 .
23. Maurya N, Awasthi S, Dixit P . Association of CFTR gene mutation with bronchial asthma . The Indian Journal of Medical Research . 135 . 4 . 469–478 . April 2012 . 22664493 . 3385229 . 2019-03-16 . dead . https://web.archive.org/web/20200312193126/https://icmr.nic.in/ijmr/2012/april/0404.pdf . 2020-03-12 .
24. https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQUEST=CCDS&DATA=CCDS5773.1 CCDS Report for Consensus CDS: Report for CCDS5773.1 (current version)
25. Bartoszewski RA, Jablonsky M, Bartoszewska S, Stevenson L, Dai Q, Kappes J, Collawn JF, Bebok Z . A synonymous single nucleotide polymorphism in DeltaF508 CFTR alters the secondary structure of the mRNA and the expression of the mutant protein . The Journal of Biological Chemistry . 285 . 37 . 28741–28748 . September 2010 . 20628052 . 2937902 . 10.1074/jbc.M110.154575 . free .
26. Web site: Re: Is there a connection between cystic fibrosis and cholera?.
27. Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G, Ratcliff R, Evans MJ, Colledge WH . Salmonella typhi uses CFTR to enter intestinal epithelial cells . Nature . 393 . 6680 . 79–82 . May 1998 . 9590693 . 10.1038/30006 . 5894247 . 1998Natur.393...79P .
28. Dahl M, Nordestgaard BG, Lange P, Tybjaerg-Hansen A . Fifteen-year follow-up of pulmonary function in individuals heterozygous for the cystic fibrosis phenylalanine-508 deletion . The Journal of Allergy and Clinical Immunology . 107 . 5 . 818–823 . May 2001 . 11344348 . 10.1067/mai.2001.114117 . free .
29. Dahl M, Tybjaerg-Hansen A, Lange P, Nordestgaard BG . DeltaF508 heterozygosity in cystic fibrosis and susceptibility to asthma . Lancet . 351 . 9120 . 1911–1913 . June 1998 . 9654257 . 10.1016/s0140-6736(97)11419-2 . 22970136 .
30. Wang X, Kim J, McWilliams R, Cutting GR . Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation . Archives of Otolaryngology–Head & Neck Surgery. 131 . 3 . 237–240 . March 2005 . 15781764 . 10.1001/archotol.131.3.237 . free .
31. https://www.cysticfibrosis.org.uk/~/media/documents/the-work-we-do/uk-cf-registry/ecfs-annual-report--what-it-means-to-the-uk-v7.ashx?la=en ECFS Annual Report: What It Means to the UK
32. Morral N, Bertranpetit J, Estivill X, Nunes V, Casals T, Giménez J, Reis A, Varon-Mateeva R, Macek M, Kalaydjieva L . The origin of the major cystic fibrosis mutation (delta F508) in European populations . Nature Genetics . 7 . 2 . 169–175 . June 1994 . 7920636 . 10.1038/ng0694-169 . 38005421 .
33. Web site: Cystic Fibrosis Mutation Database . Genomic DNA sequence . 2013-04-06 . https://web.archive.org/web/20160822142645/http://www.genet.sickkids.on.ca/GenomicDnaSequencePage.html . 2016-08-22 . dead .
34. Web site: CFTR . 2022-10-09 . Johns Hopkins Cystic Fibrosis Center . en-US.
35. Sheppard DN, Welsh MJ . Structure and function of the CFTR chloride channel . Physiological Reviews . 79 . 1 Suppl . S23–S45 . January 1999 . 9922375 . 10.1152/physrev.1999.79.1.S23 . free .
36. Zhang Z, Liu F, Chen J . Molecular structure of the ATP-bound, phosphorylated human CFTR . Proceedings of the National Academy of Sciences of the United States of America . 115 . 50 . 12757–12762 . December 2018 . 30459277 . 6294961 . 10.1073/pnas.1815287115 . 2018PNAS..11512757Z . free .
37. Zhang Z, Liu F, Chen J . Conformational Changes of CFTR upon Phosphorylation and ATP Binding . Cell . 170 . 3 . 483–491.e8 . July 2017 . 28735752 . 10.1016/j.cell.2017.06.041 . 5361509 . free .
38. Sheppard DN, Welsh MJ . Structure and function of the CFTR chloride channel . Physiological Reviews . 79 . 1 Suppl . S23–S45 . January 1999 . 9922375 . 10.1152/physrev.1999.79.1.S23 . free .
39. Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL . An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton . The Journal of Biological Chemistry . 273 . 31 . 19797–19801 . July 1998 . 9677412 . 10.1074/jbc.273.31.19797 . free .
40. Vergani P, Lockless SW, Nairn AC, Gadsby DC . CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains . Nature . 2005 . 433 . 7028 . 876–80 . 10.1038/nature03313 . 15729345 . 2756053 . 2005Natur.433..876V . 4383918 .
41. Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A . Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways . Histochemistry and Cell Biology . 137 . 3 . 339–353 . March 2012 . 22207244 . 10.1007/s00418-011-0904-1 . 15178940 .
42. Sharma S, Hanukoglu A, Hanukoglu I . Localization of epithelial sodium channel (ENaC) and CFTR in the germinal epithelium of the testis, Sertoli cells, and spermatozoa . Journal of Molecular Histology . 49 . 2 . 195–208 . April 2018 . 29453757 . 10.1007/s10735-018-9759-2 . 3761720 .
43. Sharma S, Hanukoglu I . Mapping the sites of localization of epithelial sodium channel (ENaC) and CFTR in segments of the mammalian epididymis . Journal of Molecular Histology . 50 . 2 . 141–154 . April 2019 . 30659401 . 10.1007/s10735-019-09813-3 . 58026884 .
44. Web site: CF Study Finds New Cells Called Ionocytes Carrying High levels of CFTR Gene . Cystic Fibrosis News Today . 3 August 2018.
45. Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, Yuan F, Chen S, Leung HM, Villoria J, Rogel N, Burgin G, Tsankov AM, Waghray A, Slyper M, Waldman J, Nguyen L, Dionne D, Rozenblatt-Rosen O, Tata PR, Mou H, Shivaraju M, Bihler H, Mense M, Tearney GJ, Rowe SM, Engelhardt JF, Regev A, Rajagopal J . A revised airway epithelial hierarchy includes CFTR-expressing ionocytes . Nature . 560 . 7718 . 319–324 . August 2018 . 30069044 . 6295155 . 10.1038/s41586-018-0393-7 . 2018Natur.560..319M .
46. Plasschaert LW, Žilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, Klein AM, Jaffe AB . A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte . Nature . 560 . 7718 . 377–381 . August 2018 . 30069046 . 6108322 . 10.1038/s41586-018-0394-6 . 2018Natur.560..377P .
47. Hanukoglu I, Boggula VR, Vaknine H, Sharma S, Kleyman T, Hanukoglu A . Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages . Histochemistry and Cell Biology . 147 . 6 . 733–748 . June 2017 . 28130590 . 10.1007/s00418-016-1535-3 . 8504408 .
48. Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B . A novel host defense system of airways is defective in cystic fibrosis . American Journal of Respiratory and Critical Care Medicine . 175 . 2 . 174–183 . January 2007 . 17082494 . 2720149 . 10.1164/rccm.200607-1029OC .
49. Xu Y, Szép S, Lu Z . The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases . Proceedings of the National Academy of Sciences of the United States of America . 106 . 48 . 20515–20519 . December 2009 . 19918082 . 2777967 . 10.1073/pnas.0911412106 . free . 2009PNAS..10620515X .
50. Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S, Inagaki Y, Miyamoto K, Suzuki O, Okawa H . Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors . Liver . 12 . 2 . 90–93 . April 1992 . 1320177 . 10.1111/j.1600-0676.1992.tb00563.x .
51. Boyle MP, De Boeck K . A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect . The Lancet. Respiratory Medicine . 1 . 2 . 158–163 . April 2013 . 24429096 . 10.1016/s2213-2600(12)70057-7 .
52. Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA . Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator . The Journal of Biological Chemistry . 277 . 32 . 28948–28958 . August 2002 . 12039948 . 10.1074/jbc.M111706200 . free .
53. Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB . A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression . The Journal of Biological Chemistry . 277 . 5 . 3520–3529 . February 2002 . 11707463 . 10.1074/jbc.M110177200 . free .
54. Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR . The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins . The Journal of Biological Chemistry . 278 . 8 . 6440–6449 . February 2003 . 12471024 . 10.1074/jbc.M211050200 . free .
55. Wang S, Yue H, Derin RB, Guggino WB, Li M . Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity . Cell . 103 . 1 . 169–179 . September 2000 . 11051556 . 10.1016/S0092-8674(00)00096-9 . 16697781 . free .
56. Liedtke CM, Yun CH, Kyle N, Wang D . Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor . The Journal of Biological Chemistry . 277 . 25 . 22925–22933 . June 2002 . 11956211 . 10.1074/jbc.M201917200 . free .
57. Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL . CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex . Proceedings of the National Academy of Sciences of the United States of America . 99 . 19 . 12477–12482 . September 2002 . 12209004 . 129470 . 10.1073/pnas.192203899 . free . 2002PNAS...9912477C .
58. Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I . The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3 . The Journal of Biological Chemistry . 277 . 52 . 50503–50509 . December 2002 . 12403779 . 10.1074/jbc.M201862200 . free .
59. Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, Szabó K, Homolya L, Milgram SL, Sarkadi B . C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins . Biochemical and Biophysical Research Communications . 302 . 3 . 454–461 . March 2003 . 12615054 . 10.1016/S0006-291X(03)00196-7 .
60. Wang S, Raab RW, Schatz PJ, Guggino WB, Li M . Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR) . FEBS Letters . 427 . 1 . 103–108 . May 1998 . 9613608 . 10.1016/S0014-5793(98)00402-5 . 20803242 . free .
61. Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA . The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane . The Journal of Biological Chemistry . 275 . 35 . 27069–27074 . September 2000 . 10852925 . 10.1074/jbc.M004951200 . free .
62. Hall RA, Ostedgaard LS, Premont RT, Blitzer JT, Rahman N, Welsh MJ, Lefkowitz RJ . A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins . Proceedings of the National Academy of Sciences of the United States of America . 95 . 15 . 8496–8501 . July 1998 . 9671706 . 21104 . 10.1073/pnas.95.15.8496 . free . 1998PNAS...95.8496H .
63. Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA . E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells . The Journal of Biological Chemistry . 275 . 38 . 29539–29546 . September 2000 . 10893422 . 10.1074/jbc.M004961200 . free .
64. Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, Benos DJ, Quick MW, Kirk KL . Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms . Nature . 390 . 6657 . 302–305 . November 1997 . 9384384 . 10.1038/36882 . 4395005 . 1997Natur.390..302N .
65. Egan ME . Genetics of Cystic Fibrosis: Clinical Implications . Clinics in Chest Medicine . 37 . 1 . 9–16 . March 2016 . 26857764 . 10.1016/j.ccm.2015.11.002 .
66. De Boeck K, Amaral MD . Progress in therapies for cystic fibrosis . The Lancet. Respiratory Medicine . 4 . 8 . 662–674 . August 2016 . 27053340 . 10.1016/S2213-2600(16)00023-0 .
67. Thiagarajah JR, Verkman AS . CFTR inhibitors for treating diarrheal disease . Clinical Pharmacology and Therapeutics . 92 . 3 . 287–290 . September 2012 . 22850599 . 3643514 . 10.1038/clpt.2012.114 .
68. Jones AM, Helm JM . Emerging treatments in cystic fibrosis . Drugs . 69 . 14 . 1903–1910 . October 2009 . 19747007 . 10.2165/11318500-000000000-00000 . 23344660 .
69. McPhail GL, Clancy JP . Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis . Drugs of Today . 49 . 4 . 253–260 . April 2013 . 23616952 . 10.1358/dot.2013.49.4.1940984 .
70. Web site: Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation . 2011-02-23 . Cystic Fibrosis Foundation . Press Release .
71. Web site: The Most Important New Drug Of 2012 . Forbes . Herper M . 27 December 2012 .
72. Web site: The $300,000 Drug . 18 July 2014 . . Nocera J .