title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
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.
authors.affiliation: 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.
authors.forename: Elma
authors.initials: E
authors.lastname: El Khouri
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Thomas
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jeanson
authors.affiliation: 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.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bequignon
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Vallette
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Paris 75012, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Montantin
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Dastot-Le Moal
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Blanchon
authors.affiliation: 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.
authors.forename: Jean François
authors.initials: JF
authors.lastname: Papon
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lorès
authors.affiliation: Savaid School of Medicine and College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Collot
authors.affiliation: Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tissier
authors.affiliation: Laboratoire de Microscopie Electronique, Service d'Anatomopathologie, Centre Hospitalier Intercommunal de Créteil, Créteil 94000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Faucon
authors.affiliation: 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.
authors.forename: Gérard
authors.initials: G
authors.lastname: Gacon
authors.affiliation: Service de Biologie de la Reproduction, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Université Paris Diderot, Sorbonne Paris Cité, Paris 75018, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Patrat
authors.affiliation: 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.
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Wolf
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dulioust
authors.affiliation: Service de Pneumologie A, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris 75018, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Crestani
authors.affiliation: 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.
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.affiliation: 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.
authors.forename: André
authors.initials: A
authors.lastname: Coste
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Legendre
authors.affiliation: 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: aminata.toure@inserm.fr.
authors.forename: Aminata
authors.initials: A
authors.lastname: Touré
authors.affiliation: 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.
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000293:Adolescent; D051017:Apoptosis Regulatory Proteins; D054468:Axoneme / Q000235:genetics; D002923:Cilia / Q000235:genetics; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005260:Female; D005407:Flagella / Q000235:genetics / Q000473:pathology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D007619:Kartagener Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D012326:RNA Splicing / Q000235:genetics; D012661:Semen; D013094:Spermatozoa / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C477075:DNAJB13 protein, human; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex
keywords: DNAJB13; PCD; central complex; cilia; radial spoke; sperm flagellum