The cystic fibrosis transmembrane conductance regulator (CFTR, ATP-binding cassette sub-family C, member 7, ABCC7) protein is 1480 amino acids in length. It is encoded by a single large gene with 27 exons spanning around 250kbp on chromosome 7q31.2, identified in the search to find the gene underlying cystic fibrosis (CF) disease [1–4]. The protein structure is made up of two units, each with six transmembrane helices and an intracellular nucleotide-binding domain (NBD) that can interact with adenosine triphosphate (ATP). A regulatory “R” domain connects the two units and contains sites for protein kinase phosphorylation [1]. The structure creates a channel in the plasma membrane through which anions can flow, and the gate is thought to be opened and closed by ATP binding and hydrolysis (NBDs) and phosphorylation mechanisms (R domain) which alter the protein’s conformation [1, 5, 6]. CFTR is expressed predominantly in epithelial tissues, but is also found in other cell types such as smooth muscle, cardiac myocytes, macrophages, and erythrocytes [1]. CFTR is multi-functional. It is an anion channel that transports chloride (Cl−) and bicarbonate. It is also involved in the regulation of a range of transporters including the epithelial sodium channel (ENaC encoded by SCNN1A, SCNN1B, SCNN1D and SCNN1G) and outwardly rectifying chloride channels (ORCC) [1, 7–10]. In addition, CFTR has been proposed to be a hub for signaling pathways and may regulate a variety of other physiological processes including exocytosis and endocytosis, ATP export, proinflammatory cytokine expression and intracellular pH [1, 10]. Defective CFTR therefore results in widespread cellular homeostasis dysfunction [10]. CF is an autosomal recessive disease resulting from a defect-causing variant on each CFTR allele. More than 1800 variants in the CFTR gene have been reported [11]. Despite a large collection of variants, there is a gap in our knowledge regarding which cause CF disease. To address this, the Clinical and Functional Translation of CFTR project was established to collect information regarding the functional consequences and resulting phenotypes associated with CFTR variants [12, 13]. Data for 39,696 subjects from 25 CF patient registries or specialty clinics were collected for the database, and an initial set of 159 CFTR variants (those with a frequency of ≥0.01% in the CFTR2 database) was evaluated for whether they cause CF disease by both clinical phenotype and functional analysis [12]. A variant was defined clinically as causing CF if mean sweat chloride concentration was ≥60mM for at least three individuals with the variant or >90mM if only 2 individuals with the variant were available; 140 variants met the clinical criteria to be CF-causing. The variants were sorted by their predicted functional effect, and 77 were investigated further using in vitro assays appropriate to the genetic variant (<10% of wild-type CFTR function was considered disease-causing); 133 variants were deemed CF-causing by functional criteria. In total, 127 variants met both the clinical and functional criteria, and were defined as CF-causing. Penetrance analysis in fathers with CF children was carried out on the variants that did not meet both/either criteria and 12 variants were deemed non-CF causing, with the remaining 20 variants indeterminate [12, 13]. CF is a disease that predominantly affects the lungs but has a diverse array of phenotypes due to the expression of CFTR in different tissues, its wide-ranging physiological role, and its involvement in many signaling pathways [1, 7, 10]. Progressive lung disease, pancreatic dysfunction, infertility in males and elevated sweat electrolytes characterize a “classical” CF diagnosis [14]. CF is also associated with a reduced life expectancy (early adulthood) and an increased risk of cancer [1, 10]. There is, however, wide variability in clinical presentation, severity and the rate of disease progression between patients, which can be influenced by the underlying CFTR genotype as well as other genetic modifiers and environmental factors [1, 7, 10, 14–17]. The incidence of CF is thought to be around 70,000 cases worldwide [18], though it may be largely under-diagnosed in parts of Asia, Africa and Latin America [14, 19]. Genetic testing is now a routine part of CF diagnosis in many countries. A recommended panel for genetic screening for determining prenatal and preconception carrier status of CF in the US includes 23 CFTR variants, designed to cover variants with a frequency of at least 0.1% in CF patients that are associated with classical CF disease, for a pan-ethnic US population [20–22]. The WHO recommends sequencing of the complete CFTR gene in CF patients from populations where CF is likely under-diagnosed in order to establish panels of population-specific variants known to cause disease [14].
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Open Access
Apr 1, 2015
Jordan Bunda + 2
