PDF version - Cftrscience

Transcription

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Key points
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Normal cystic fibrosis transmembrane conductance regulator (CFTR) protein channels transport ions, such as chloride and
bicarbonate, through the apical 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 glands1,2
The CFTR gene, located on chromosome 7, encodes the CFTR protein1
The presence of CFTR mutations on both alleles generally results in cystic fibrosis2
References:
1. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117‐133.
2. 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.
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Key points
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The CFTR gene encodes a CFTR protein channel that is made up of 1480 amino acids organized into 5 functional domains1,2:
− 2 membrane-spanning domains (MSD1 and MSD2) also known as transmembrane domains (TMD1 and TMD2)3
• The MSDs are each composed of 6 transmembrane segments, forming the CFTR channel pore2
– 2 nucleotide-binding domains (NBD1 and NBD2)
• NBDs interact with nucleotides to regulate channel activity—opening and closing of the MSDs2,3
– 1 regulatory domain (R), which also controls channel activity2
References:
1. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001.
2. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell.
1993;73(7):1251-1254.
3. Patrick AE, Thomas PJ. Development of CFTR structure. Front Pharmacol. 2012;3:162. doi:10/3389/fphar.2012.00162.
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Key points
The CFTR protein reaches the apical epithelial cell membrane as part of a multistep process. As with all proteins, this process involves1-4:
• Synthesis (transcription and translation)
• Folding and processing
• Trafficking to its destination (e.g., apical cell membrane)
• Turnover
CFTR protein synthesis1
• In the nucleus, the CFTR gene is transcribed into mRNA
• Introns (noncoding sequences) are then removed from mRNA during a process called splicing
• The protein is synthesized in the cytoplasm and enters the endoplasmic reticulum (ER) during synthesis
CFTR protein folding and processing2,3,5
• Immature CFTR protein is folded and processed in the ER
• Any protein that does not fold properly is degraded
CFTR protein trafficking2,5
• CFTR protein is transported to the Golgi apparatus for final processing and then the mature protein is trafficked to the cell surface
CFTR protein function4,6
• At the cell surface, CFTR proteins function as channels that transport chloride and bicarbonate ions
CFTR protein turnover3
• CFTR channels have a limited lifespan and are eventually removed in a process called turnover
When protein synthesis, folding and processing, and trafficking occur properly, fully functional CFTR proteins reach the cell surface in sufficient
quantity to maintain adequate ion transport.1-4
References:
1. Strachan T, Read AP. Chapter 1: DNA structure and gene expression. In: Human Molecular Genetics. 2nd ed. New York, NY: Wiley‐Liss;
1999. http://www.ncbi.nlm.nih.gov/books/NBK7585. Accessed December 15, 2014.
2. Cooper GM. Chapter 9: Protein sorting and transport. In: The Cell: A Molecular Approach. 2nd ed. Washington, DC: ASM Press; 2000.
3. Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1994;269(41):
25710-25718.
5. Mall M, Kreda SM, Mengos A, et al. The DeltaF508 mutation results in loss of CFTR function and mature protein in native human colon.
Gastroenterology. 2004;126(1):32-41.
6. 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.
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Key points
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CFTR quantity is determined by1,2:
– CFTR synthesis: CFTR gene transcription, proper splicing, and mRNA translation
– CFTR processing and trafficking: maturation of the CFTR protein and its delivery to the cell surface
– CFTR surface stability: amount of time a CFTR channel is at the cell surface before being removed and
recycled
References:
2. Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. J Biol Chem.
1994;269(41): 25710-25718.
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Key points
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CFTR proteins function as channels that transport ions through the apical cell membrane of epithelial cells1
CFTR protein function is determined by channel-open probability (gating) and conductance1,2
– Channel-open probability: the fraction of time that a single CFTR protein channel is open and transporting ions2
• Based on in vitro experimentation, normal CFTR channels have channel-open probability of ~40%3
– Channel conductance: rate at which ions move through open channels2
References:
2. 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.
3. 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.
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Key points
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Total CFTR activity can be defined as total ion transport mediated by CFTR protein channels at the cell surface. Total CFTR activity is
determined by1-4:
– CFTR quantity: the number of CFTR channels at the cell surface
– CFTR function: the functional ability of each channel to open and transport ions
References:
1. 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. .
3. Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 1994;269(41):2571025718.
4. 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.
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Key points
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The CFTR gene is expressed in epithelial tissue of multiple organs throughout the body. The cystic fibrosis transmembrane conductance
regulator, or CFTR, channel plays an important role in maintaining electrolytes and fluid balance in many organ systems1-5
– The regulated transport of electrolytes and fluid is necessary for the proper function of the airway, pancreas, gastrointestinal tract,
and sweat glands, among others
– In individuals without CF, normal expression of CFTR protein and normal CFTR activity contribute to the proper function of these
organs
References:
2. Ramsey B, Richardson MA. Impact of sinusitis in cystic fibrosis. J Allergy Clin Immunol. 1992;90(3 Pt 2):547-552.
3. 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.
4. 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.
5. Quinton PM. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 1990;4(10):2709-2717.
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Key points
Approximately 2000 mutations in the CFTR gene have been identified to date, although the majority are extremely rare.1-15
• F508del is the most common CFTR mutation worldwide
− Up to 91% of patients with CF have an F508del mutation on at least one allele, based on individual country registries3-15
– This frequency varies among countries and ethnic groups
• 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
• Frequency and mutational diversity vary among countries
• About 23 mutations in total occur at a frequency of >0.1%
Not all CFTR mutations lead to CF. To date, only 127 CFTR mutations have been confirmed as CF-causing.1
References:
1. 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.
2. 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.
3. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual Data Report. Bethesda, MD. © 2013 Cystic
Fibrosis Foundation.
4. Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry 2012‒15th Annual Report. © 2013; Cystic Fibrosis Australia; Baulkham
Hills NSW, Australia.
5. Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2012 Annual Report. Toronto, ON: Cystic Fibrosis Canada; 2014.
6. European Cystic Fibrosis Society. ECFS Patient Registry 2010 Annual Data Report. 2014.
7. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2).
http://www.cftr2.org. Accessed November 20, 2014.
8. Brazilian Cystic Fibrosis Study Group. Brazilian Cystic Fibrosis Patient Registry 2010 Annual Report. São Paulo, Brazil; 2012.
9. Belgian Cystic Fibrosis Registry. The Belgian Cystic Fibrosis Registry 2010 Summary Report. Brussels, Belgium: Scientific Institute of
Public Health; 2012.
10. Cystic Fibrosis Trust. UK Cystic Fibrosis Registry Annual Data Report 2012. © 2013: Cystic Fibrosis Trust; London, UK.
11. French Cystic Fibrosis Registry. 2011 Annual Report 2012. © Vaincre le Mucoviscidose and Ined. 2014; Paris, France.
12. The Cystic Fibrosis Registry of Ireland. 2012 Annual Report. © CFRI, 2014; Dublin, Ireland.
13. Mukoviszidose e.V. und Mukoviszidose Institut gemeinnützige Gesselschaft für Forschung und Therapienntwicklung mbH. Beriichtsband
Qualitätssicherung Mukoviszidose 2012. © 2013, Bonn, Germany.
14. Cystic Fibrosis Association of New Zealand. Port CFNZ National Data Registry 2012 Report. Christchurch, New Zealand; 2013.
15. Netherlands Cystic Fibrosis Registry. Dutch CF Registry 2012 Annual Report. Baarn, the Netherlands; 2013.
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Key points
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Cystic fibrosis (CF) is a common autosomal recessive disorder affecting approximately 70,000 people worldwide. The majority of
people with CF are of Caucasian descent, therefore the disease is most prevalent in North American, European, and Australasian
populations. However, CF can affect all races and ethnicities, including African, Latin American, and Middle Eastern populations1-3
The prevalence of CF and spectrum of CFTR mutations vary considerably among populations and regions of the world1
References:
1. World Health Organization. The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of
WHO/ECFTN/ICF(M)A/ECFS; June19, 2002; Genoa, Italy. © World Health Organization; 2004.
2. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual Data Report. Bethesda, MD. © 2013 Cystic
Fibrosis Foundation.
3. US Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. Facts About
Cystic Fibrosis. NIH Publication No. 95-3650. November 1995. Accessed: December 18, 2014.
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Key points
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Different mutations in the CFTR gene can cause disruptions at various stages of CFTR protein synthesis or in several aspects of CFTR
protein function. They can result in less CFTR protein at the cell surface, virtual absence of CFTR protein, or dysfunctional CFTR
protein at the cell surface1
Traditionally, the CFTR class system groups CFTR mutations by the primary molecular defect in the CFTR protein. Although each
mutation is categorized by a single defect, an individual mutation can result in multiple defects, spanning multiple classes1-3
– Class I: defective synthesis of full-length CFTR protein. Premature stop codon prevents full translation of mRNA, resulting in
truncated CFTR protein. Few to no mature CFTR proteins are formed
– Class II: defective CFTR protein processing and trafficking. Defective post-translational processing and transport reduce quantity
of CFTR protein delivered to cell surface
– Class III: defective CFTR channel gating. CFTR is at the cell surface but has reduction in channel-open probability
– Class IV: defective CFTR channel conductance. CFTR is at the cell surface but has impaired movement of ions through channel
– Class V: reduced synthesis of CFTR protein. A splicing defect reduces quantity of properly processed CFTR mRNA transcripts,
decreasing quantity of CFTR protein at the cell surface
– Class VI: reduced stability of CFTR protein. Accelerated turnover of CFTR protein at the cell surface reduces quantity
References:
1. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133.
2. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254.
3. 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.
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Key points
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Loss of CFTR protein activity is the underlying cause of CF1,2
– Individual CFTR mutations can lead to decreased quantity or function (and sometimes both) of CFTR proteins at the epithelial cell
surface
– These defects in CFTR proteins limit ion transport through the apical cell membrane
Defective ion transport in the lungs, pancreas, gastrointestinal (GI) system, sinuses, sweat glands, and reproductive system leads to the
symptoms of CF1-5
– The resulting imbalance of fluid and electrolytes causes thick, sticky mucus (in lungs, sinuses) or viscous secretions (in pancreas,
GI tract, reproductive tract) to accumulate, which interferes with the proper function of these organs
– Defective chloride ion transport in the sweat gland leads to high salt concentration in sweat, but does not impact the morphology of
the gland
References:
2. Orenstein DM, Spahr JE, Weiner DJ. Cystic Fibrosis: A Guide for Patient and Family. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2012.
4. 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.
www.ommbid.com.
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Key points
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Total CFTR activity is a function of how each CFTR mutation affects1:
– CFTR quantity: the number of CFTR channels at the cell surface
– CFTR function: the functional ability of each channel to open and transport ions
Individual CFTR mutations can decrease the quantity or function (and sometimes both) of CFTR proteins at the cell surface. These
defects in CFTR protein cause a reduction in total CFTR activity1-3
References:
1. Sheppard DN, Rich DP, Ostedgaard LS, Gregory RJ, Smith AE, Welsh MJ. Mutation in CFTR associated with mild-disease-form Clchannels with altered pore properties. Nature. 1993;362(6416):160-164.
3. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254.
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Key points
Some CFTR mutations reduce CFTR protein quantity or function at the cell surface to such an extent that the result is little to no CFTR
activity.1-4
• CFTR mutations that cause a defect in protein synthesis due to nonsense mutations (e.g., G542X) or a splicing abnormality that results
in a premature stop codon (e.g., 621+1G->T) result in few to no CFTR proteins at the cell surface
• CFTR mutations that affect processing (e.g., F508del) result in few to no CFTR proteins delivered to the cell surface
• CFTR mutations that produce CFTR proteins with decreased stability (e.g., 4326delTC) result in functional CFTR channels that rapidly
degrade at the cell surface, leaving few to no CFTR proteins at the cell surface
• CFTR mutations that severely affect gating (e.g., G551D) or conductance (e.g., R334W) result in a normal quantity of CFTR channels
at the cell surface that have little to no function
References:
3. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):
1251-1254.
4. Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL. C-terminal truncations destabilize the cystic fibrosis transmembrane
conductance regulator without impairing its biogenesis. A novel class of mutation. J Biol Chem. 1999;274(31):21873-21877.
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Key points
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Some CFTR mutations result in a limited reduction in CFTR protein quantity or function at the cell surface that can produce residual or
partial CFTR activity1-3:
– Some CFTR mutations that cause a defect in mRNA splicing (e.g., 2789+5G->A) can result in reduced protein synthesis but
delivery of some functional CFTR proteins to the cell surface
– CFTR mutations that reduce conductance and/or gating (e.g., R117H) can result in a normal quantity of CFTR channels at the
cell surface that have some level of function and ion transport
References:
3. 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.
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Key point
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The potential clinical impact of an individual CFTR mutation may be related to the amount of total CFTR ion transport activity. Total CFTR
activity is associated with the extent of CF manifestations and phenotypic variability1-5
References:
2. 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.
3. Rowe SM, Accurso F, Clancy JP. Detection of cystic fibrosis transmembrane conductance regulator activity in early-phase clinical trials.
Proc Am Thorac Soc. 2007;4(4):387-398.
4. Davis PB, Drumm M, Konstan MW. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256.
5. Bombieri C, Claustres M, De Boeck K, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros.
2011;10(Suppl 2). doi:10.1016/S1569-1993(11)60014-3.
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Key points
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The degree to which a CFTR mutation reduces CFTR quantity or function (or both) at the cell surface determines the total CFTR
activity of the cell1,2
Total CFTR activity can be defined as total ion transport mediated by CFTR protein channels at the cell surface1
The potential clinical impact of an individual CFTR mutation may be related to the amount of total CFTR ion transport activity. Total
CFTR activity is associated with the extent of CF manifestations and phenotypic variability2-6
References:
3. 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.
6. Bombieri C, Claustres M, De Boeck K, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst
Fibros. 2011;10(Suppl 2). doi:10.1016/S1569-1993(11)60014-3.
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Key points
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Total CFTR activity, which is mainly determined by CFTR genotype, is one of a few factors that influence the phenotype of an individual
and determines if he or she will develop CF disease and to what degree1-3
– The mutations present on both CFTR alleles determine CFTR protein production and activity
Individuals with 2 normal (wild-type) CFTR alleles produce CFTR proteins of normal quantity and function, and therefore, sufficient
activity1,4,5
– These individuals neither have nor are carriers of CF
Carriers of CF have 1 normal CFTR allele, which produces normal CFTR protein, and 1 mutated CFTR allele, which produces defective
CFTR protein with reduced quantity or function1,4,5
– In this case, there is sufficient functional CFTR protein, and hence CFTR activity, to result in a non-CF phenotype
– Nonetheless, some carriers may have increased risk for certain pulmonary conditions (e.g., asthma)
People who have CF-causing mutations on both alleles produce CFTR proteins that are defective in quantity or function (and
sometimes both), leading to a reduction of total CFTR activity and a CF phenotype1-3
Other factors that may contribute to a cystic fibrosis phenotype include:
• Modifier genes: may affect lung function and disease course1,6
 Examples include key factors of the immune system, mannose-binding lectin 2 (MBL2) and transforming growth factor beta 1
(TGF-ß1)
• Environmental factors: can also significantly affect phenotype. Examples may include1,2,6-8 :
 Level of care/socioeconomic status
 Nutritional status
 Exposure to cigarette smoke and other pollutants
 Age at onset of lung infection
References:
J Cyst Fibros. 2008;7(3):179-196.
6. Knowles MR, Drumm M. The influence of genetics on cystic fibrosis phenotypes. Cold Spring Harb Perspect Med. 2012;2(12):1-13.
7. 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.
8. 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.
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Key points
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CFTR mutations on both alleles contribute to the quantity of functional CFTR proteins and respective levels of total CFTR activity1-4
– CFTR mutations can result in either little to no CFTR protein activity or in residual CFTR protein activity
– The extent to which the combination of CFTR alleles affects CFTR protein activity (i.e., normal, residual, little to no) influences
the phenotype of an individual person
References:
J Cyst Fibros. 2008;7(3):179-196.
4. 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.
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Key points
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G542X is an example of a mutation resulting in little to no CFTR activity. In combination with another allele that produces little to no CFTR
activity, G542X usually results in a CF phenotype1-5
The CFTR2 database is the primary source for this composite CF phenotype of patients who have a G542X mutation on 1 allele and a
pancreatic insufficient mutation on the second allele. These patients exhibit the following characteristics1:
– Elevated sweat chloride (average): 102 mmol/L
– Lung function decline over time
– Pseudomonas colonization: 56% of patients
– Pancreatic insufficiency: 96% of patients
References:
1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional Translation of CFTR (CFTR2).
2. DeGracia J, Mata F, Alvarez A, et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005;60(7):558-563.
3. Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. N Eng J Med.
1993;329(18):1308-1313.
4. Davis PB, Drumm M, Konstan MW, et al. Cystic fibrosis. Am J Respir Crit Care Med. 1996;154(5):1229-1256.
5. Castellani C, Cuppens H, Mazek 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.
24
Key points
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3849+10kbCT is an example of a mutation resulting in residual CFTR activity. In combination with another allele that produces little
to no CFTR activity, 3849+10kbC T can result in CF symptoms that may emerge later in life1-5
The CFTR2 database is the primary source for this composite CF phenotype of patients who have a 3849+10kbCT mutation on 1
allele and a pancreatic insufficient mutation on the second allele. These patients exhibit the following characteristics1:
– Elevated sweat chloride (average): 67 mmol/L
– Late onset of CF lung disease compared to homozygous F508del patients2
– Pseudomonas colonization: 57% of patients
– Pancreatic insufficiency: 32% of patients
References:
1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional Translation of CFTR (CFTR2).
2. Duguépéroux I, De Braekeleer M. The CFTR 3849+10kbC->T and 2789+5G->A alleles are associated with a mild CF phenotype. Eur
Respir J. 2005;25(3):468-473.
3. Highsmith WE Jr, Burch LH, Zhou Z, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal
sweat chloride concentrations. N Engl J Med. 1994;331(15):974-980.
4. DeGracia J, Mata F, Alvarez A, et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005;60(7):558563.
5. Castellani C, Cuppens H, Mazek 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.
25
Key points
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Cystic fibrosis, a systemic, multiorgan disease, is caused by loss of CFTR protein-mediated ion transport (activity)1-5
– 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
– In the sweat glands, loss of CFTR activity restricts reabsorption of chloride in the duct, limiting the amount of salt that can be
reabsorbed
Symptoms of CF manifest throughout life with great variability among patients, though lung disease is the primary cause of mortality1,5-7
References:
1. Zielenski J. Genotype and phenotype in cystic fibrosis. Respiration. 2000;67(2):117-133.
2. Orenstein DM, Spahr JE, Weiner DJ. Cystic Fibrosis: A Guide for Patient and Family. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2012.
4. O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373(9678):1891-1904.
www.ommbid.com.
6. European Cystic Fibrosis Society. ECFS Patient Registry 2010 Annual Data Report. 2014.
7. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2012 Annual Data Report. Bethesda, MD. © 2013 Cystic Fibrosis
Foundation.
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