Did you know...

Figure 1. Pathogenesis of lung disease in Cystic Fibrosis 3

...that lung disease is the main cause of morbidity and mortality in cystic fibrosis (CF)?

CF is one of the most common lethal genetic disorders affecting primarily Caucasians and populations of European descent [1, 2]. The disease is one of abnormal ion transport. It is caused by mutations in a gene located on the short arm of chromosome 7, which encodes for a glycoprotein known as Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) [4]. In 1985, scientists used a positional cloning approach termed "reverse genetics" to locate the position of the CF gene. The novel molecular tool entailed first identifying the location of a gene, then working backward to understand the physiologic bases of the disease [5]. In 1989, laboratories of Drs. Lap-Che Tsui, John Riordan, and Francis Collins simultaneously reported in Science the identification of the mutated gene present on chromosomes of CF patients compared to normal patients [6-8]. Today, almost 2,000 mutations have been identified (www.genet.sickkids.on.ca/cftr) with the most common being a deletion of phenylalanine at position 508 [5]. The mutations can be ascribed to five categories which encompass reductions in mRNA levels, protein production, protein processing, channel regulation, and channel conduction [1]. Physiological results of the mutations are an impairment of salt and water transport across the apical membrane of epithelial cells in sweat glands, reproductive and gastrointestinal systems and the respiratory tract [9]. This results in organ failure and subsequent death, except in the case of sweat glands. Complications from lung disease are the most common cause of mortality. The lung disease profile is a combination of mucus hypersecretion and impaired mucociliary clearance to form an abnormal airway surface environment conducive to chronic airway infections and bronchiectasis. [3] (Figure 1).

Over 20 years since the discovery of the mutated gene, the disease remains uncured. Modern treatments of symptoms, but not the underlying defect, have managed to increase life expectancy to about 37 years [10]. The current therapeutic aim is to correct the underlying genetic defect by targeting lung epithelial cells to introduce a normal CFTR gene or to potentiate the CFTR channel conductance using pharmacological agents. [9, 11] Hope remains to manage the various aspects of the lung disease in an attempt to extend patients' lives to a level comparable to the rest of the population.

References

  1. Rosenstein BJ, Zeitlin PL. Cystic fibrosis. Lancet 1998;351:277-82.
  2. Ratjen F, Doring G. Cystic fibrosis. Lancet 2003;361:681-9.
  3. Dinwiddie R. Pathogenesis of lung disease in cystic fibrosis. Respiration 2000;67:3-8.
  4. Tsui LC. The cystic fibrosis transmembrane conductance regulator gene. Am J Respir Crit Care Med 1995;151:S47-53.
  5. Welsh MJ, Ramsey BW. Research on cystic fibrosis: a journey from the Heart House. Am J Respir Crit Care Med 1998;157:S148-54.
  6. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80.
  7. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066-73.
  8. Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989;245:1059-65.
  9. Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. Pharmacol Ther 2010;125:219-29.
  10. Simmonds NJ, Cullinan P, Hodson ME. Growing old with cystic fibrosis - the characteristics of long-term survivors of cystic fibrosis. Respir Med 2009;103:629-35.
  11. Van Goor F, Hadida S, Grootenhuis PD, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 2009;106:18825-30.

Author: Pierre Kadeba
Chief editor: Natalie Bauer, Ph.D., April 2013

 

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