What is the role of normal CFTR protein channels?Normal CFTR protein channels transport ions, such as chloride and bicarbonate, through the cell membrane of epithelial cells. This helps to regulate fluid and electrolyte balance in epithelial tissues throughout the body, such as in the lungs, sinuses, pancreas, intestine, reproductive system, and sweat glands. Without proper ion flow, the ionic concentration of secretions changes. The epithelia can no longer maintain surface hydration and the duct lumens may become obstructed.1,2
What is total CFTR activity?Total CFTR activity can be defined as total ion transport mediated by CFTR protein channels at the cell surface.3
What determines total CFTR activity?
Which processes assure sufficient quantity of normal CFTR proteins at the cell surface?CFTR quantity is determined by1,5:
What processes affect the function of normal CFTR protein?
How often does the normal CFTR protein channel open?Based on in vitro experimentation, normal CFTR channels have channel-open probability of ~40%—meaning they are open approximately 40% of the time.6
What are the physiological effects of normal CFTR activity?
How many known mutations are there in the CFTR gene?Approximately 2000 mutations in the CFTR gene have been identified to date, although the majority are extremely rare.10
Do all CFTR mutations cause cystic fibrosis (CF)?Not all CFTR mutations cause CF. To date, only 127 CFTR mutations have been confirmed as CF-causing.10
What CFTR mutations occur with enough frequency to be considered “common”?F508del is the most common CFTR mutation worldwide: up to 88% of people with CF have an F508del mutation on at least one allele. Although occurring at a much lower frequency than F508del, the following 11 mutations occur at a frequency of >1% globally: G542X, G551D, R117H, N1303K, W1282X, R553X, 621+1G->T, 1717-1G->A, 3849+10kbC->T, 2789+5G->A, and 3120+1G->A. Another 3 mutations occur at a frequency of >1% in Canada, Europe, and Australia, but not in the United States: 711+1G->T, 2183AA->G, and R1162X. About 23 mutations in total occur at a frequency of >0.1%. Other mutations are even more rare.11-15
In what regions of the world is cystic fibrosis (CF) most prevalent?
How does the structure of the CFTR protein channel relate to its function?The CFTR protein channel is organized into 5 functional domains17-19:
What is the purpose of the CFTR Mutation Class System?The CFTR Mutation Class System groups CFTR mutations by the mutation’s primary molecular defect in the CFTR protein.1,18
What is the molecular defect associated with Class I CFTR mutations?
What is the molecular defect associated with Class II CFTR mutations?A Class II CFTR mutation leads to defective CFTR protein processing and trafficking. Defective folding most likely causes abnormal post-translational processing of the CFTR protein. These proteins are not effectively transported to the cell surface and the quantity of CFTR protein at the cell surface is reduced.1,18
What is the molecular defect associated with Class III CFTR mutations?
What is the molecular defect associated with Class IV CFTR mutations?
What is the molecular defect associated with Class V CFTR mutations?
What is the molecular defect associated with Class VI CFTR mutations?
Is there a way to categorize CFTR mutations other than the CFTR Mutation Class System?
One can also think about CFTR mutations as affecting either the quantity or function of CFTR proteins. Mutations associated with defects in CFTR protein synthesis, defects in folding and trafficking, and defects in stability could be considered defects in quantity. Defects in function include reduced channel-open probability and reduced conductance.1,18,20
Another way to group CFTR mutations is by their effect on total CFTR activity. Individual CFTR mutations can result in little to no (i.e., minimal) total CFTR activity or they can allow some residual (i.e., partial) CFTR function. The combination of mutations on both alleles determines total CFTR activity.1,3,21
Can a CFTR mutation result in more than one type of CFTR defect—affecting both quantity and function?An individual mutation can result in multiple CFTR protein defects, spanning multiple classes and affecting both quantity and function. One example is the F508del mutation, known as a Class II mutation and associated with a molecular defect in processing and trafficking of CFTR protein (quantity). However, uncorrected F508del-CFTR protein also has a Class III defect in channel-open probability (function) and a Class VI defect in stability that accelerates turnover of CFTR protein at the cell surface (quantity).18,22
What is the underlying cause of cystic fibrosis (CF) symptoms and disease progression?Loss of CFTR protein activity—ion transport—is the underlying cause of CF symptoms. Defective ion transport in the lungs, pancreas, gastrointestinal system, sinuses, skin, and reproductive system leads to the symptoms of CF. The resulting imbalance of fluid and electrolytes has physiological effects that interfere with the proper function of multiple organs.1,2,8,9,23
How do CFTR mutations affect total CFTR activity?Total CFTR activity can be defined as total ion transport mediated by CFTR protein channels at the cell surface. The degree to which the CFTR mutation reduces CFTR quantity and/or function determines the total CFTR activity of the cell. Some CFTR mutations result in little to no total CFTR activity, while others still allow partial or residual total CFTR activity.1,3,21
How does loss of CFTR protein activity in people with cystic fibrosis (CF) cause the characteristic accumulation of thick mucus in multiple organs?CF, a systemic, multiorgan disease, is caused by loss or reduction of CFTR protein-mediated ion transport (activity). Defective ion transport leads to an imbalance of fluid and electrolytes, causing thick, sticky mucus and viscous secretions to accumulate in different organs. This interferes with the proper function of the lungs, pancreas, gastrointestinal system, sinuses, and reproductive system.1,2,8,23,24
What is the relationship between CFTR genotype and phenotype?CFTR genotype determines the quantity or function of CFTR protein, which in turn determines total CFTR ion transport activity through the apical epithelial surface. Generally, 2 CFTR mutations that produce little to no CFTR activity are associated with early evidence of disease progression, while 1 or 2 CFTR mutations that allow partial or residual total CFTR activity lead to a delayed onset of CF symptoms or CF-related disorder.1,3,21,25-27
Is CFTR genotype the only predictor of phenotype?Modifier genes and environmental factors also influence the clinical phenotype in individuals with CF, contributing to the variability of symptoms among patients. Modifier genes, such as mannose-binding lectin 2 (MBL2) and transforming growth factor-beta 1 (TGF-β1), can significantly affect pulmonary disease course. Selected environmental factors include level of care and socioeconomic status, nutritional status, exposure to cigarette smoke and other pollutants, and age at onset of lung infection.1,25,28-30
- Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117‐133.
- Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis: membrane transport disorders. In: Valle D, Beaudet A, Vogelstein B, et al, eds. The Online Metabolic & Molecular Bases of Inherited Disease. The McGraw‐Hill Companies Inc; 2004:part 21, chap 201. www.ommbid.com.
- Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature. 1993;362(6416):160-164.
- Wang W, Linsdell P. Conformational change opening the CFTR chloride channel pore coupled to ATP-dependent gating. Biochim Biophys Acta. 2012;1818(3):851-860.
- Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1994;269(41):25710-25718.
- Bompadre SG, Sohma Y, Li M, Hwang TC. G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects. J Gen Physiol. 2007;129(4):285-298.
- Ramsey B, Richardson MA. Impact of sinusitis in cystic fibrosis. J Allergy Clin Immunol. 1992;90(3 Pt 2):547-552.
- Moskowitz SM, Chmiel JF, Sternen DL, et al. Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders. Genet Med. 2008;10(12):851-868.
- Quinton PM. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 1990;4(10):2709-2717.
- Sosnay PR, Siklosi KR, Van Goor F, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013;45(10):1160-1167.
- Amos J, Feldman GL, Grody WW, et al; American College of Medical Genetics Laboratory Quality Assurance Committee. Standards and Guidelines for Clinical Genetics Laboratories. 2008 ed. http://www.acmg.net. Revised March 2011.
- Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual Data Report. Bethesda, MD. © 2013 Cystic Fibrosis Foundation.
- Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry 2012—15th Annual Report. © 2013; Cystic Fibrosis Australia; Baulkham Hills NSW, Australia.
- Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2012 Annual Report. Toronto, ON: Cystic Fibrosis Canada; 2014.
- European Cystic Fibrosis Society. ECFS Patient Registry 2010 Annual Data Report. 2014.
- World Health Organization. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS; June 19, 2002; Genoa, Italy. © World Health Organization; 2004.
- Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001.
- Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254.
- Patrick AE, Thomas PJ. Development of CFTR structure. Front Pharmacol. 2012;3:162. doi:10/3389/fphar.2012.00162.
- Wang Y, Wrennall JA, Cai Z, Li H, Sheppard DN. Understanding how cystic fibrosis mutations disrupt CFTR function: from single molecules to animal models. Int J Biochem Cell Biol. 2014;52C:47-57. doi:10.1016/j.biocel.2014.04.001.
- Green DM, McDougal KE, Blackman SM, et al. Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients. Respir Res. 2010;11(140). doi:10.1186/1465-9921-11-140.
- Hegedus T, Aleksandrov A, Cui L, Gentzsch M, Chang X-B, Riordan JR. F508del CFTR with two altered RXR motifs escapes from ER quality control but its channel activity is thermally sensitive. Biochim Biophys Acta. 2006;1758(5):565-572.
- Orenstein DM, Spahr JE, Weiner DJ. Cystic Fibrosis: A Guide for Patient and Family. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
- O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-1904.
- Castellani C, Cuppens H, Macek M, et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008;7(3):179-196.
- Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. The Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med. 1993;329(18):1308-1313.
- McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003;361(9370):1671-1676.
- Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012;2(12):1-13.
- Quittner AL, Schechter MS, Rasouliyan L, Haselkorn T, Pasta DJ, Wagener JS. Impact of socioeconomic status, race, and ethnicity on quality of life in patients with cystic fibrosis in the United States. Chest. 2010;137(3):642-650.
- Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr. 2007;151(2):134-139.