title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
abstract: Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive condition resulting from structural and/or functional defects of the axoneme in motile cilia and sperm flagella. The great majority of mutations identified so far involve genes whose defects result in dynein-arm anomalies. By contrast, PCD due to CC/RS defects (those in the central complex [CC] and radial spokes [RSs]), which might be difficult to diagnose, remains mostly unexplained. We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects. RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells. Its protein product, which localizes within the cilia of respiratory epithelial cells, was undetectable in airway cells from an individual with RSPH3 mutations and in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia. In the case of RSPH3 mutations, high-speed-videomicroscopy analyses revealed the coexistence of immotile cilia and motile cilia with movements of reduced amplitude. A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects. Overall, this study shows that RSPH3 mutations contribute to disease in more than 10% of PCD-affected individuals with CC/RS defects, thereby allowing an accurate diagnosis to be made in such cases. It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans.
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jeanson
authors.affiliation: Service de Génétique et 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 S955, Equipe 13, Université Paris-Est Créteil, 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: Service de Génétique et 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), Sorbonne Universités, Paris 75012, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.affiliation: Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Montantin
authors.affiliation: Service de Pneumologie-Centre Expert Maladies Pulmonaires Rares, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris 75020, France; Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75020, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.affiliation: Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris and Centre National de Référence des Maladies Respiratoires Rares, Paris 75012, France; INSERM UMR S938, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.affiliation: INSERM UMR S955, Equipe 13, Université Paris-Est Créteil, Créteil 94000, France; Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Hôpital Intercommunal et 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: Département de Génétique Médicale, Université Libre de Bruxelles and Hôpital Erasme, Brussels 1020, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Désir
authors.affiliation: Service d'Oto-Rhino-Laryngologie, Hôpital Universitaire des Enfants Reine Fabiola, Brussels 1020, Belgium.
authors.forename: Anissa
authors.initials: A
authors.lastname: Souayah
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Kott
authors.affiliation: Service de Génétique et 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 Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Tissier
authors.affiliation: INSERM UMR S955, Equipe 13, Université Paris-Est Créteil, Créteil 94000, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Louis
authors.affiliation: Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris and Centre National de Référence des Maladies Respiratoires Rares, Paris 75012, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Tamalet
authors.affiliation: Service de Pneumologie et Allergologie Pédiatriques, Groupe Hospitalier Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris and Université Paris Descartes, Paris 75015, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: de Blic
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris and Centre National de Référence des Maladies Respiratoires Rares, Paris 75012, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France. Electronic address: serge.amselem@inserm.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.affiliation: INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Legendre
mesh_terms: D002923:Cilia / Q000235:genetics* / Q000648:ultrastructure; D020022:Genetic Predisposition to Disease; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics* / Q000473:pathology*; D018715:Microscopy, Video; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype
chemical_list: D009419:Nerve Tissue Proteins; C544862:RSPH3 protein, human