title: DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis.
abstract: OBJECTIVE
  Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients is associated with worse long-term pulmonary disease and shorter survival, and chronic Pa infection (CPA) is associated with reduced lung function, faster rate of lung decline, increased rates of exacerbations and shorter survival. By using exome sequencing and extreme phenotype design, it was recently shown that isoforms of dynactin 4 (DCTN4) may influence Pa infection in CF, leading to worse respiratory disease. The purpose of this study was to investigate the role of DCTN4 missense variants on Pa infection incidence, age at first Pa infection and chronic Pa infection incidence in a cohort of adult CF patients from a single centre.
  
  
  METHODS
  Polymerase chain reaction and direct sequencing were used to screen DNA samples for DCTN4 variants.
  
  
  RESULTS
  A total of 121 adult CF patients from the Cochin Hospital CF centre have been included, all of them carrying two CFTR defects: 103 developed at least 1 pulmonary infection with Pa, and 68 patients of them had CPA. DCTN4 variants were identified in 24% (29/121) CF patients with Pa infection and in only 17% (3/18) CF patients with no Pa infection. Of the patients with CPA, 29% (20/68) had DCTN4 missense variants vs 23% (8/35) in patients without CPA. Interestingly, p.Tyr263Cys tend to be more frequently observed in CF patients with CPA than in patients without CPA (4/68 vs 0/35), and DCTN4 missense variants tend to be more frequent in male CF patients with CPA bearing two class II mutations than in male CF patients without CPA bearing two class II mutations (P = 0.06).
  
  
  CONCLUSIONS
  Our observations reinforce that DCTN4 missense variants, especially p.Tyr263Cys, may be involved in the pathogenesis of CPA in male CF.
authors.affiliation: AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Viel
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Hubert
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Pierre-Regis
authors.initials: PR
authors.lastname: Burgel
authors.affiliation: Inserm U1078, Génétique, Génomique fonctionnelle et Biotechnologies, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Honoré
authors.affiliation: AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Martinez
authors.affiliation: AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Gaitch
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Chapron
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Reem
authors.initials: R
authors.lastname: Kanaan
authors.affiliation: Service de Pneumologie, GH Cochin-Broca-Hôtel Dieu, Université Paris Descartes, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dusser
authors.affiliation: AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girodon
authors.affiliation: AP-HP, Laboratoire de Biochimie et Génétique Moléculaire, Groupe Universitaire Paris Centre, Paris, France. thierry.bienvenu@inserm.fr.|Institut Cochin, INSERM U1016, Université Paris Descartes, Paris, France. thierry.bienvenu@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003545:Cysteine / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics* / Q000382:microbiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D000072159:Dynactin Complex / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011552:Pseudomonas Infections / Q000235:genetics* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D012189:Retrospective Studies; D012737:Sex Factors; D014443:Tyrosine / Q000378:metabolism; D055815:Young Adult
chemical_list: C505032:CFTR protein, human; C000606363:DCTN4 protein, human; D000072159:Dynactin Complex; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014443:Tyrosine; D003545:Cysteine
keywords: DCTN4; cystic fibrosis; dynactin 4; modifier gene - Pseudomonas aeruginosa infection