long, and creates a protein that is 1,480 amino acids long. more specifically, the location is between base pair 117,120,016 and 117,308,718 on the long arm of chromosome 7, region 3, band 1, subband 2, represented as 7q31.2. structurally, the cftr is a type of gene known as an abc gene. the product of this gene (the cftr protein) is a chloride ion channel important in creating sweat, digestive juices, and mucus. this protein possesses two atp-hydrolyzing domains, which allows the protein to use energy in the form of atp. it also contains two domains comprising six alpha helices apiece, which allow the protein to cross the cell membrane. a regulatory binding site on the protein allows activation by phosphorylation, mainly by camp-dependent protein kinase. the carboxyl terminal of the protein is anchored to the cytoskeleton by a pdz domain interaction. the majority of cftr in the lung's passages is produced by rare ion-transporting cells that regulate mucus properties. in addition, the evidence is increasing that genetic modifiers besides cftr modulate the frequency and severity of the disease. one example is mannan-binding lectin, which is involved in innate immunity by facilitating phagocytosis of microorganisms. polymorphisms in one or both mannan-binding lectin alleles that result in lower circulating levels of the protein are associated with a threefold higher risk of end-stage lung disease, as well as an increased burden of chronic bacterial infections. carriers up to one in 25 individuals of northern european ancestry is considered a genetic carrier. the disease appears only when two of these carriers have children, as each pregnancy between them has a 25% chance of producing a child with the disease. although only about one of every 3,000 newborns of the affected ancestry has cf, more than 900 mutations of the gene that causes cf are known. current tests look for the most common mutations. the mutations screened by the test vary according to a person's ethnic group or by the occurrence of cf already in the family. more than 10 million americans, including one in 25 white americans, are carriers of one mutation of the cf gene. cf is present in other races, though not as frequently as in white individuals. about one in 46 hispanic americans, one in 65 african americans, and one in 90 asian americans carry a mutation of the cf gene. pathophysiology the cftr protein is a channel protein that controls the flow of h2o and cl− ions in and out of cells inside the lungs. when the cftr protein is working correctly, ions freely flow in and out of the cells. however, when the cftr protein is malfunctioning, these ions cannot flow out of the cell due to a blocked channel. this causes cystic fibrosis, characterized by the buildup of thick mucus in the lungs. several mutations in the cftr gene can occur, and different mutations cause different defects in the cftr protein, sometimes causing a milder or more severe disease. these protein defects are also targets for drugs which can sometimes restore their function. δf508-cftr gene mutation, which occurs in >90% of patients in the u.s., creates a protein that does not fold normally and is not appropriately transported to the cell membrane, resulting in its degradation. other mutations result in proteins that are too short (truncated) because production is ended prematurely. other mutations produce proteins that do not use energy (in the form of atp) normally, do not allow chloride, iodide, and thiocyanate to cross the membrane appropriately, and degrade at a faster rate than normal. mutations may also lead to fewer copies of the cftr protein being produced. the protein created by this gene is anchored to the outer membrane of cells in the sweat glands, lungs, pancreas, and all other remaining exocrine glands in the body. the protein spans this membrane and acts as a channel connecting the inner part of the cell (cytoplasm) to the surrounding fluid. this channel is primarily responsible for controlling the movement of halide anions from inside to outside of the cell; however, in the sweat ducts, it facilitates the movement of chloride from the sweat duct into the cytoplasm. when the cftr protein does not resorb ions in sweat ducts, chloride and thiocyanate released from sweat glands are trapped inside the ducts and pumped to the skin. additionally hypothiocyanite, oscn, cannot be produced by the immune defense system. because chloride is negatively charged, this modifies the electrical potential inside and outside the cell that normally causes cations to cross into the cell. sodium is the most common cation in the extracellular space. the excess chloride within sweat ducts prevents sodium resorption by epithelial sodium channels and the combination of sodium and chloride creates the salt, which is lost in high amounts in the sweat of individuals with cf. this lost salt forms the basis for the sweat test. most of the damage in cf is due to blockage of the narrow passages of affected organs with thickened secretions. these blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, blockage of the intestines by thick feces, etc. several theories have been posited on how the defects in the protein and cellular function cause the clinical effects. the most current theory suggests that defective ion transport leads to dehydration in the airway epithelia, thickening mucus. in airway epithelial cells, the cilia exist in between the cell's apical surface and mucus in a layer known as airway surface liquid (asl). the flow of ions from the cell and into this layer is determined by ion channels such as cftr. cftr not only allows chloride ions to be drawn from the cell and into the asl, but it also regulates another channel called enac, which allows sodium ions to leave the asl and enter the respiratory epithelium. cftr normally inhibits this channel, but if the cftr is defective, then sodium flows freely from the asl and into the cell. as water follows sodium, the depth of asl will be depleted and the cilia will be left in the mucous layer. as cilia cannot effectively move in a thick, viscous environment, mucociliary clearance is deficient and a buildup of mucus occurs, clogging small airways. the accumulation of more viscous, nutrient-rich mucus in the lungs allows bacteria to hide from the body's immune system, causing repeated respiratory infections. the presence of the same cftr proteins in the pancreatic duct and sweat glands in the skin also cause symptoms in these systems. chronic infections the lungs of individuals with cystic fibrosis are colonized and infected by bacteria from an early age. these bacteria, which often spread among individuals with cf, thrive in the altered mucus, which collects in the small airways of the lungs. this mucus leads to the formation of bacterial microenvironments known as biofilms that are difficult for immune cells and antibiotics to penetrate. viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. the natural history of cf lung infections and airway remodeling is poorly understood, largely due to the immense spatial and temporal heterogeneity both within and between the microbiomes of cf patients. over time, both the types of bacteria and their individual characteristics change in individuals with cf. in the initial stage, common bacteria such as s. aureus and h. influenzae colonize and infect the lungs. eventually, pseudomonas aeruginosa (and sometimes burkholderia cepacia) dominates. by 18 years of age, 80% of patients with classic cf harbor p. aeruginosa, and 3.5% harbor b. cepacia. once within the lungs, these bacteria adapt to the environment and develop resistance to commonly used antibiotics. pseudomonas can develop special characteristics that allow the formation of large colonies, known as "mucoid" pseudomonas, which are rarely seen in people who do not have cf. scientific evidence suggests the interleukin 17 pathway plays a key role in resistance and modulation of the inflammatory response during p. aeruginosa infection in cf. in particular, interleukin 17-mediated immunity plays a double-edged activity during chronic airways infection; on one side, it contributes to the control of p. aeruginosa burden, while on the other, it propagates exacerbated pulmonary neutrophilia and tissue remodeling. infection can spread by passing between different individuals with cf. in the past, people with cf often participated in summer "cf camps" and other recreational gatherings. hospitals grouped patients with cf into common areas and routine equipment (such as nebulizers) was not sterilized between individual patients. this led to transmission of more dangerous strains of bacteria among groups of patients. as a result, individuals with cf are now routinely isolated from one another in the healthcare setting, and healthcare providers are encouraged to wear gowns and gloves when examining patients with cf to limit the spread of virulent bacterial strains. cf patients may also have their airways chronically colonized by filamentous fungi (such as aspergillus fumigatus, scedosporium apiospermum, aspergillus terreus) and/or yeasts (such as candida albicans); other filamentous fungi less commonly isolated include aspergillus flavus and aspergillus nidulans (occur transiently in cf respiratory secretions) and exophiala dermatitidis and scedosporium prolificans (chronic airway-colonizers); some filamentous fungi such as penicillium emersonii and acrophialophora fusispora are encountered in patients almost exclusively in the context of cf. defective mucociliary clearance characterizing cf is associated with local immunological disorders. in addition, the prolonged therapy with antibiotics and the use of corticosteroid treatments may also facilitate fungal growth. although the clinical relevance of the fungal airway colonization is still a matter of debate, filamentous fungi may contribute to the local inflammatory response and therefore to the progressive deterioration of the lung function, as often happens with allergic bronchopulmonary aspergillosis – the most common fungal disease in the context of cf, involving a th2-driven immune response to aspergillus species. diagnosis the location of the cftr gene on chromosome 7 in many localities all newborns are screened for cystic fibrosis within the first few days of life, typically by blood test for high levels of immunoreactive trypsinogen. newborns with positive tests or those who are otherwise suspected of having cystic fibrosis based on symptoms or family history, then undergo a sweat test. an electric current is used to drive pilocarpine into the skin, stimulating sweating. the sweat is collected and analyzed for salt levels. having unusually high levels of chloride in the sweat suggests cftr is dysfunctional; the person is then diagnosed with cystic fibrosis. genetic testing is also available to identify the cftr mutations typically associated with cystic fibrosis. many laboratories can test for the 30–96 most common cftr mutations, which can identify over 90% of people with cystic fibrosis. people with cf have less thiocyanate and hypothiocyanite in their saliva and mucus (banfi et al.). in the case of milder forms of cf, transepithelial potential difference measurements can be helpful. cf can also be diagnosed by identification of mutations in the cftr gene. in many cases, a parent makes the diagnosis because the infant tastes salty. immunoreactive trypsinogen levels can be increased in individuals who have a single mutated copy of the cftr gene (carriers) or, in rare instances, in individuals with two normal copies of the cftr gene. due to these false positives, cf screening in newborns can be controversial. by 2010 every us state had instituted newborn screening programs and as of 2016, 21 european countries had programs in at least some regions. prenatal women who are pregnant or couples planning a pregnancy can have themselves tested for the cftr gene mutations to determine the risk that their child will be born with cf. testing is typically performed first on one or both parents and, if the risk of cf is high, testing on the fetus is performed. the american college of obstetricians and gynecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier. because development of cf in the fetus requires each parent to pass on a mutated copy of the cftr gene and because cf testing is expensive, testing is often performed initially on one parent. if testing shows that parent is a cftr gene mutation carrier, the other parent is tested to calculate the risk that their children will have cf. cf can result from more than a thousand different mutations. as of 2016,