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Cystic fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study
  1. Margarida D Amarala,b,
  2. Paula Pachecoa,
  3. Sebastian Becka,
  4. Carlos M Farinhaa,b,
  5. Deborah Penquea,
  6. Paulo Nogueirac,
  7. Celeste Barretod,
  8. Beatriz Lopese,
  9. Teresa Casalsf,
  10. Javier Dapenag,
  11. Silvia Gartnerh,
  12. Carlos Vásquezi,
  13. Javier Pérez-Fríasj,
  14. Casilda Olveiraj,
  15. Rodrigo Cabanask,
  16. Xavier Estivillf,
  17. Maria Tzetisl,
  18. Emmanuel Kanavakisl,
  19. Stavros Doudounakisl,
  20. Thilo Dörkm,
  21. Burkhard Tümmlerm,
  22. Emmanuelle Girodon-Boulandetn,
  23. Cécile Cazeneuven,
  24. Michel Goossensn,
  25. Martine Blayauo,
  26. Claudine Verlinguep,
  27. Isabel Vieirap,
  28. Claude Férécp,
  29. Mireille Claustresq,
  30. Marie des Georgesq,
  31. Christine Clavelr,
  32. Philippe Birembautr,
  33. Dominique Huberts,
  34. Thierry Bienvenut,
  35. Michèle Adounu,
  36. Jean-Claude Chomelu,
  37. Kris De Boeckv,
  38. Harry Cuppensw,
  39. João Lavinhaa
  1. aCentro de Genética Humana, Instituto Nacional de Saúde Dr Ricardo Jorge, Av Padre Cruz, 1649-016 Lisboa, Portugal, bDepartmento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal, cObservatório Nacional de Saúde, Instituto Nacional Saúde Dr Ricardo Jorge, Lisboa, Portugal, dUnidade de Fibrose Quística, Serviço de Pediatria, Hospital de Stª Maria, Lisboa, Portugal, eHospital D Estefânia, Lisboa, Portugal, fMolecular Genetics Department-IRO, Hospital Duran I Reynals, Barcelona, Spain, gCystic Fibrosis Unit, Hospital Universitario Virgen del Rocio, Sevilla, Spain, hCystic Fibrosis Unit, Hospital Universitario Materno Infantil Vall d'Hebrón, Barcelona, Spain, iCystic Fibrosis Unit, Hospital Infantil de Cruces, Barakaldo, Vizcaya, País Vasco, Spain, jCystic Fibrosis Unit, Hospital Carlos Haya, Malaga, Spain, kPaediatric Service, Hospital Xeral, Galicia, Spain, lFirst Department of Paediatrics and Choremio Research Laboratory, Unit of Molecular Medicine, St Sophia Children's Hospital, Athens, Greece, mKlinische Forschergruppe, OE 6711, Medizinische Hochschule, Hannover, Germany, nService de Biochimie et de Génétique, Hôpital Henri Mondor, Créteil, France, oService de Génétique Moléculaire et Hormonologie, Centre Hospitalier Regional et Universitaire de Rennes Pontchaillou, Rennes, France, pLaboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire de Brest, France, qLaboratoire de Génétique Moléculaire et Chromosomique, Institut de Biologie, Montpellier, France, rLaboratoire Pol Bouin et Unité Inserm U514, Hôpital Maison Blanche, CHU Reims, France, sLaboratoire de Biochimie et Biologie Moléculaire, Groupe Hospitalier Cochin, Paris, France, tService de Pneumologie, Groupe Hospitalier Cochin, Paris, France, uLaboratoire de Génétique Céllulaire et Moléculaire, CHU de Poitiers, France, vDepartment of Paediatrics, UZ Gasthuisberg, Leuven, Belgium, wCentre for Human Genetics, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
  1. Dr Amaral, mdamaral{at}

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Editor—Cystic fibrosis (CF, MIM 219700) is a common, severe, autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene cloned in 1989.1-3The disease, characterised by chronic lung disease which is the main cause of morbidity and mortality, pancreatic dysfunction, raised electrolyte levels in sweat, and male infertility, is caused by altered chloride (Cl) secretion across the apical membrane of epithelial cells.4 There is, however, substantial variability in the clinical manifestations affecting the various organs.4 5

One single mutation, F508del, generally associated with severe disease, accounts for about 70% of CF chromosomes world wide, although with a heterogeneous geographical distribution.5 Patients homozygous for the F508del mutation have the classical severe form of the disease which includes chronic mucous obstruction of the lung and conducting airways, followed by recurrent infections mostly byPseudomonas aeruginosa (Pa) andStaphylococcus aureus (Sa), exocrine pancreatic insufficiency (PI), resulting in failure to gain weight and height, and raised levels of Cl, sodium, and potassium in exocrine sweat.5 However, almost 1000 genetic alterations have been detected in the CFTR gene (CFTR Mutation Database), most presumed to be disease causing mutations. About half of these are amino acid substitutions (missense mutations) and about 20% are splicing mutations. The remainder are nonsense, frameshift (including small deletions and insertions), and a small proportion of promoter mutations.

The relationship between genotype, that is, the mutations in theCFTR gene, and the clinical phenotype of CF patients has been difficult to establish, in particular for lung disease.

It was previously shown that the 3272-26A>G mutation leads to the creation of an alternative acceptor splice site competing with the normal one during RNA processing and resulting in the occurrence of an alternatively spliced mRNA with 25 extra nucleotides from …

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