Pathway maps

CFTR translational fidelity (class I mutations)
CFTR translational fidelity (class I mutations)

Object List (links open in MetaCore):

CFTR, PTC124, Small 40S subunit, mRNA, Large 60S subunit, DNA, <cytosol> Cl('-) = <extracellular region> Cl('-), 6.1.1.-, Gentamicin cytosol, AMP-aminoacid, tRNA, Cl('-) cytosol, aminoacid*(tRNA), Tobramycin cytosol, mRNA, mRNA, Cl('-) extracellular region, Amikacin cytosol


CFTR translational fidelity (class I mutations)

Cystic Fibrosis (CF) is a potentially lethal genetic disease that typically results in the development of bronchial inflammation, bronchiectasis, progressive loss of lung function and, ultimately, death. CF is caused by genetic defects in Cystic Fibrosis Transmembrane Conductance Regulator ( CFTR ) gene which encodes a chloride channel regulating chloride transport in the lung [1].

More than 1000 mutations of the CFTR gene have been identified so far. Studies suggested that different mutations cause defects in production and function of the CFTR protein that involve different molecular mechanisms. The mutations are classified according to their molecular pathology. Class I mutations impair protein synthesis (e.g., premature termination signals, and truncated or unstable protein) and lead to lack of CFTR chloride channels. G542X, R553X, W1282X are the examples of class I mutations [2], [3].

Aminoglycoside antibiotics (e.g., Gentamicin [4], [5], Tobramycin [4], Amikacin [6] ) reduce fidelity of translation by inhibition of the ribosomal 'proofreading'. These antibiotics bind to the specific site on the ribosomal RNA and disrupt codon-anticodon recognition at the aminoacid*(tRNA) acceptor site. This causes extensive misreading of the mRNA code, enabling insertion of alternative amino acids at the site of the mutated codon. This substitution is not fully efficient; a fraction of normal full-length transcript is produced [2].

Another drug impairing translational fidelity is the PTC124, a 284.24Da achiral, 1,2,4-oxadiazole linked to fluorobenzene and benzoic acid rings. This compound has no structural similarity to aminoglycosides or other clinically developed drugs, and its anhydrous free carboxylic acid form, despite having low aqueous solubility, is orally bioavailable when prepared in aqueous suspension. PTC124 promotes read-through of premature termination CFTR without affecting normal termination [7].


  1. Dubin PJ, McAllister F, Kolls JK
    Is cystic fibrosis a TH17 disease? Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2007 Jun;56(6):221-7
  2. Kerem E
    Pharmacologic therapy for stop mutations: how much CFTR activity is enough? Current opinion in pulmonary medicine 2004 Nov;10(6):547-52
  3. Proesmans M, Vermeulen F, De Boeck K
    What's new in cystic fibrosis? From treating symptoms to correction of the basic defect. European journal of pediatrics 2008 Aug;167(8):839-49
  4. Du M, Jones JR, Lanier J, Keeling KM, Lindsey JR, Tousson A, Beb?k Z, Whitsett JA, Dey CR, Colledge WH, Evans MJ, Sorscher EJ, Bedwell DM
    Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. Journal of molecular medicine (Berlin, Germany) 2002 Sep;80(9):595-604
  5. Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, Kerem B, Kerem E
    Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. The New England journal of medicine 2003 Oct 9;349(15):1433-41
  6. Du M, Keeling KM, Fan L, Liu X, Kova??s T, Sorscher E, Bedwell DM
    Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model. Journal of molecular medicine (Berlin, Germany) 2006 Jul;84(7):573-82
  7. Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM
    PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proceedings of the National Academy of Sciences of the United States of America 2008 Feb 12;105(6):2064-9