Editing Cystic fibrosis (section)

==Causes==
[[File:autorecessive.svg|thumb|upright=1.3|Cystic fibrosis has an autosomal recessive pattern of inheritance.]]
CF is caused by having no functional copies (alleles) of the [[gene]] [[CFTR (gene)|cystic fibrosis transmembrane conductance regulator]] (''CFTR''). As of 2018, over 1,900 mutations leading to CF have been described, but only 5 of them have a frequency greater than 1% among patients. The most common mutant allele, [[ΔF508]] (also termed F508del), is a deletion ([[delta (letter)#Mathematics and the Sciences|Δ]] signifying deletion) of three nucleotides that results in a loss of the amino-acid residue [[phenylalanine]] (F) at the 508th position of the protein.<ref name="pmid28881097">{{cite journal | vauthors = Guimbellot J, Sharma J, Rowe SM | title = Toward inclusive therapy with CFTR modulators: Progress and challenges | journal = Pediatric Pulmonology | volume = 52 | issue = S48 | pages = S4–S14 | date = November 2017 | pmid = 28881097 | pmc = 6208153 | doi = 10.1002/ppul.23773 }}</ref><ref name="pmid32512483">{{cite journal | vauthors = Sharma J, Keeling KM, Rowe SM | title = Pharmacological approaches for targeting cystic fibrosis nonsense mutations | journal = European Journal of Medicinal Chemistry | volume = 200 | pages = 112436 | date = August 2020 | pmid = 32512483 | pmc = 7384597 | doi = 10.1016/j.ejmech.2020.112436 }}</ref> This mutant allele is already present in 1 in 20 to 25 people of Northern European ancestry; it accounts for 70% of CF cases worldwide and 90% of cases in the [[United States]]; however, over 700 other mutant alleles, some of which represent new mutations, can produce CF.<ref name="prevalence">[http://www.cftr2.org/mutations_history 'CFTR2 Variant List History']</ref> Although most people have two working copies (alleles) of the ''CFTR'' gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an [[Autosomal recessive disorder#Dominant and recessive genetic diseases in humans|autosomal recessive disease]].<ref name="Lancet2016" />

The ''CFTR'' gene, found at the q31.2 [[locus (genetics)|locus]] of [[chromosome 7]], is 230,000 [[base pair]]s long, and encodes a protein that is 1,480 [[amino acid]]s 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 [[ATP-binding cassette transporter genes|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 hydrolysis|ATP-hydrolyzing]] [[Structural domain|domains]], which allows the protein to use energy in the form of [[Adenosine triphosphate|ATP]]. It also contains two domains comprising six [[Alpha helix|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]].<ref name="Rowe" /> The [[C-terminal end|carboxyl terminal]] of the protein is anchored to the [[cytoskeleton]] by a [[PDZ (biology)|PDZ]] domain interaction.<ref name="pmid9677412">{{cite journal | vauthors = Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL | title = An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton | journal = The Journal of Biological Chemistry | volume = 273 | issue = 31 | pages = 19797–19801 | date = July 1998 | pmid = 9677412 | doi = 10.1074/jbc.273.31.19797 | doi-access = free }}</ref> Most CFTR in lung passages is produced by rare ion-transporting cells that regulate mucus properties.<ref name="pmid30097657">{{cite journal | vauthors = Travaglini KJ, Krasnow MA | title = Profile of an unknown airway cell | journal = Nature | volume = 560 | issue = 7718 | pages = 313–314 | date = August 2018 | pmid = 30097657 | doi = 10.1038/d41586-018-05813-7 | doi-access = free | bibcode = 2018Natur.560..313T }}</ref>

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. [[Polymorphism (biology)|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.<ref name=kumar2007/>

===Carriers===
Up to one in 25 individuals of Northern European ancestry is considered a [[genetic carrier]].<ref name="Edwards" /> 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, since the CFTR gene's discovery in 1989, over 2,000 variants have been identified, but only about 700 of these have been recognized as responsible for causing CF.<ref name="pmid37699417">{{cite journal | vauthors = Graeber SY, Mall MA | title = The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches | journal = Lancet | volume = 402 | issue = 10408 | pages = 1185–1198 | date = September 2023 | pmid = 37699417 | doi = 10.1016/s0140-6736(23)01608-2 | s2cid = 261623275 }}</ref> Current tests look for the most common mutations.<ref name="Edwards">{{cite journal | vauthors = Edwards QT, Seibert D, Macri C, Covington C, Tilghman J | title = Assessing ethnicity in preconception counseling: genetics--what nurse practitioners need to know | journal = Journal of the American Academy of Nurse Practitioners | volume = 16 | issue = 11 | pages = 472–480 | date = November 2004 | pmid = 15617360 | doi = 10.1111/j.1745-7599.2004.tb00426.x | s2cid = 7644129 }}</ref>

The mutant alleles 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 mutant allele of the CF gene. [[Cystic fibrosis and race|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.<ref name="Edwards"/>