2. Academic Validation
  3. Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility

Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility

  • Am J Hum Genet. 2016 Aug 4;99(2):489-500. doi: 10.1016/j.ajhg.2016.06.022.
Elma El Khouri 1,  Lucie Thomas 2,  Ludovic Jeanson 2,  Emilie Bequignon 3,  Benoit Vallette 2,  Philippe Duquesnoy 2,  Guy Montantin 4,  Bruno Copin 5,  Florence Dastot-Le Moal 5,  Sylvain Blanchon 6,  Jean François Papon 7,  Patrick Lorès 1,  Li Yuan 8,  Nathalie Collot 4,  Sylvie Tissier 4,  Catherine Faucon 9,  Gérard Gacon 1,  Catherine Patrat 10,  Jean Philippe Wolf 11,  Emmanuel Dulioust 11,  Bruno Crestani 12,  Estelle Escudier 5,  André Coste 3,  Marie Legendre 5,  Aminata Touré 13,  Serge Amselem 5
Affiliations

Affiliations

  • 1 INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
  • 2 INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
  • 3 Equipe 13, INSERM UMR S955, Faculté de Médecine, Université Paris Est, Centre National de la Recherche Scientifique ERL7240, Créteil 94000, France; Service d'ORL et de Chirurgie Cervicofaciale, Centre Hospitalier Intercommunal de Créteil & Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique - Hôpitaux de Paris, Créteil 94000, France.
  • 4 Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
  • 5 INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France; Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
  • 6 INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France; Unité de Pneumologie et Allergologie Pédiatrique, Hôpital des Enfants, Centre Hospitalier Universitaire, Toulouse 31300, France.
  • 7 Equipe 13, INSERM UMR S955, Faculté de Médecine, Université Paris Est, Centre National de la Recherche Scientifique ERL7240, Créteil 94000, France; Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Maxillo-Faciale, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, Le Kremlin-Bicêtre 94275, France.
  • 8 Savaid School of Medicine and College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 9 Laboratoire de Microscopie Electronique, Service d'Anatomopathologie, Centre Hospitalier Intercommunal de Créteil, Créteil 94000, France.
  • 10 Service de Biologie de la Reproduction, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Paris 75018, France.
  • 11 Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Laboratoire d'Histologie Embryologie, Biologie de la Reproduction, Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Assistance Publique - Hôpitaux de Paris, Paris 75014, France.
  • 12 Service de Pneumologie A, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris 75018, France.
  • 13 INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. Electronic address: [email protected].
PMID: 27486783 DOI: 10.1016/j.ajhg.2016.06.022
Abstract

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ∼15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.

Keywords

DNAJB13; PCD; central complex; cilia; radial spoke; sperm flagellum.

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