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CFTR
CF transmembrane conductance regulator
The CFTR gene provides instructions for the CFTR protein, a chloride channel crucial for maintaining fluid balance and the production of thin, free-flowing mucus in various bodily systems. The CFTR gene encodes the Cystic Fibrosis Transmembrane Conductance Regulator protein, which acts as a channel across cell membranes, regulating the transport of chloride ions.
CFTR is located on the long (q) arm of chromosome 7, at band 7q31.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The CFTR gene, also known as the Cystic Fibrosis Transmembrane Conductance Regulator gene, plays a crucial role in managing the movement of ions and water across cellular membranes [PMID:8528247]. It produces a protein that acts as a channel, primarily facilitating the transport of chloride ions. This function is vital for maintaining appropriate hydration across multiple organ systems. Dysfunctional CFTR protein, often due to genetic changes, can disrupt ion transport, leading to thickened secretions. These thick secretions can then block ducts and passages, particularly within the respiratory, digestive, and reproductive systems. The CFTR gene is well-known for its association with cystic fibrosis, an inherited condition that affects various bodily systems.
What the gene does
Operating as a chloride channel within cellular membranes, the CFTR protein is embedded in cells that generate various secretions including mucus, sweat, saliva, tears, and digestive enzymes [PMID:1680288]. Negatively charged chloride particles move bidirectionally through this channel, a process that fundamentally governs how water distributes itself across tissue barriers. Proper hydration of mucus secretions depends directly on this ion movement. Beyond its chloride-handling duties, the CFTR protein modulates how other cellular channels behave, particularly those managing positively charged sodium particles that cross membranes [PMID:2570460]. Such coordination proves essential for organs like the lungs and pancreas to work correctly. When CFTR operates normally, secretions remain sufficiently fluid to coat and shield airway surfaces, digestive tract linings, reproductive passages, and additional tissue structures throughout the body. Defective CFTR disrupts the delicate balance of ion and water distribution, resulting in abnormally viscous secretions.
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Chromosome location
The CFTR gene is situated on the long arm (q) of chromosome 7, specifically at position 7q31.2. The complete CFTR protein consists of 1480 amino acids. This genomic location is consistent across the human population.
Protein structure
The CFTR protein is a complex molecule featuring several distinct functional domains. It contains two ABC transmembrane type-1 domains: ABC transmembrane type-1 1, found at amino acids 81-365, and ABC transmembrane type-1 2, located between amino acids 859-1155. Additionally, it has two ABC transporter domains: ABC transporter 1 (amino acids 423-646) and ABC transporter 2 (amino acids 1210-1443). A critical regulatory element is the Disordered R region, positioned between amino acids 654-831. Other notable regions include an interaction site with GORASP2 from amino acids 1386-1480, a general Disordered region at amino acids 1452-1480, and a PDZ-binding motif at the C-terminus, specifically amino acids 1478-1480.
Key variants
The CFTR gene can carry a wide variety of genetic changes, including those that alter single amino acids (the building blocks of proteins) or involve small deletions of DNA. Over 1,000 distinct variants have been identified in individuals with cystic fibrosis. The most frequently observed variant, known as delta F508, involves the deletion of one amino acid at position 508 within the CFTR protein, which significantly impairs its function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1204G>T | p.Glu402Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cystic fibrosis |
c.1767-2A>C | - | Pathogenic | ★★☆☆ | Cystic fibrosis |
c.1894_1895del | p.Glu632fs | Pathogenic | ★★☆☆ | Cystic fibrosis |
c.2147_2149delinsGG | p.Lys716fs | Pathogenic | ★★☆☆ | CFTR-related disorder |
c.2340_2346del | p.Gln781fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cystic fibrosis |
c.2384del | p.Ser795fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cystic fibrosis |
c.2672del | p.Asp891fs | Pathogenic/Likely pathogenic | ★★☆☆ | CFTR-related disorder |
c.508del | p.Arg170fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cystic fibrosis |
c.580-1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cystic fibrosis |
c.709C>T | p.Gln237Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CFTR-related disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the CFTR gene are primarily associated with cystic fibrosis, a serious inherited condition impacting multiple organ systems. These variants can lead to the production of thick, sticky mucus, predominantly affecting the lungs and digestive system. CFTR variants are also implicated in Congenital bilateral absence of vas deferens, a condition affecting male fertility. Additionally, some specific CFTR variants have been linked to hereditary pancreatitis and other isolated digestive or respiratory issues.
Inheritance pattern
Conditions caused by pathogenic CFTR variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the CFTR gene is reviewed by NHS England's Genomic Medicine Service, reflecting its clinical importance. It is included on several NHS Genomic Medicine Service clinical panels, such as 'Additional findings reproductive carrier status', 'Cholestasis', 'COVID-19 research', 'Cystic fibrosis diagnostic test', 'Foetal anomalies', 'Neonatal cholestasis', 'Non-CF bronchiectasis', 'Pancreatitis', and 'Respiratory ciliopathies including non-CF bronchiectasis'. This broad inclusion highlights its significance in diagnosing and understanding various inherited conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for all individuals, particularly those with genetic predispositions or certain health conditions. For those with CFTR-related conditions, supportive lifestyle practices may include regular physical activity to help clear airways and support overall respiratory health. A balanced diet is important, and for specific conditions like cystic fibrosis, dietary modifications, often including enzyme supplementation, may be necessary to support digestion and nutrient absorption. Hydration is also crucial to help thin secretions in the body. Individuals should consult with their healthcare team for personalised lifestyle advice tailored to their specific CFTR-related condition.
Supplement considerations
There is no conclusive evidence that specific supplements can prevent CFTR-related conditions. However, for individuals diagnosed with conditions like cystic fibrosis, nutrient deficiencies are common due to malabsorption. In such cases, supplementation with fat-soluble vitamins (A, D, E, K) and sometimes other vitamins or minerals may be recommended by a healthcare professional as part of their treatment plan. Individuals should discuss any supplement use with their doctor or a registered dietitian before starting to ensure it is appropriate and safe for their specific health needs.
Frequently asked questions
What is the primary function of the CFTR gene?
The CFTR gene provides instructions for making the CFTR protein, which acts as a channel across cell membranes. Its main role is to transport chloride ions, helping to regulate water movement in tissues and produce thin, free-flowing mucus.
What conditions are associated with variants in the CFTR gene?
Variants in the CFTR gene are primarily associated with cystic fibrosis and Congenital bilateral absence of vas deferens. They can also be linked to conditions such as hereditary pancreatitis and other isolated digestive or respiratory issues.
What is the most common variant in the CFTR gene?
The most common variant identified in people with cystic fibrosis is called delta F508. This variant involves the deletion of one amino acid at position 508 in the CFTR protein, which significantly impairs its function.
Where is the CFTR gene located?
The CFTR gene is located on chromosome 7, specifically on the long arm at band 7q31.2. This location is consistent across the human genome.
How does CFTR affect mucus?
The CFTR protein's role in coordinating ion and water movement across cell membranes helps keep mucus at the right consistency. This ensures mucus remains hydrated and can properly coat and protect tissue surfaces.
References
- Deignan JL, Astbury C, Cutting GR. CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics. 2020. PMID: 32404922
- Ratbi I, Legendre M, Niel F. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Human reproduction (Oxford, England). 2007. PMID: 17329263
- Taulan M, Girardet A, Guittard C. Large genomic rearrangements in the CFTR gene contribute to CBAVD. BMC medical genetics. 2007. PMID: 17448246
- Gadsby DC, Vergani P, Csanády L. The ABC protein turned chloride channel whose failure causes cystic fibrosis. Nature. 2006. PMID: 16554808
- Cohn JA. Reduced CFTR function and the pathobiology of idiopathic pancreatitis. Journal of clinical gastroenterology. 2005. PMID: 15758663
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. The New England journal of medicine. 2005. PMID: 15888700
- Nick JA, Rodman DM. Manifestations of cystic fibrosis diagnosed in adulthood. Current opinion in pulmonary medicine. 2005. PMID: 16217177
- Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms in male infertility. International journal of andrology. 2004. PMID: 15379964
- 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. 2003. PMID: 12503104
- Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2002. PMID: 15463806
- Noone PG, Knowles MR. 'CFTR-opathies': disease phenotypes associated with cystic fibrosis transmembrane regulator gene mutations. Respiratory research. 2001. PMID: 11737931
- Adam MP, Bick S, Mirzaa GM. Cystic Fibrosis. 1993. PMID: 20301428