2. Academic Validation
  3. RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes

  • Am J Hum Genet. 2015 Jul 2;97(1):153-62. doi: 10.1016/j.ajhg.2015.05.004.
Ludovic Jeanson 1,  Bruno Copin 2,  Jean-François Papon 3,  Florence Dastot-Le Moal 2,  Philippe Duquesnoy 1,  Guy Montantin 2,  Jacques Cadranel 4,  Harriet Corvol 5,  André Coste 6,  Julie Désir 7,  Anissa Souayah 8,  Esther Kott 1,  Nathalie Collot 2,  Sylvie Tissier 2,  Bruno Louis 9,  Aline Tamalet 10,  Jacques de Blic 11,  Annick Clement 12,  Estelle Escudier 13,  Serge Amselem 14,  Marie Legendre 13
Affiliations

Affiliations

  • 1 INSERM UMR S933, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
  • 2 Service de Génétique et Embryologie Médicales, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris 75012, France.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 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.
  • 7 Département de Génétique Médicale, Université Libre de Bruxelles and Hôpital Erasme, Brussels 1020, Belgium.
  • 8 Service d'Oto-Rhino-Laryngologie, Hôpital Universitaire des Enfants Reine Fabiola, Brussels 1020, Belgium.
  • 9 INSERM UMR S955, Equipe 13, Université Paris-Est Créteil, Créteil 94000, France.
  • 10 Service de Pneumologie Pédiatrique, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris and Centre National de Référence des Maladies Respiratoires Rares, Paris 75012, France.
  • 11 Service de Pneumologie et Allergologie Pédiatriques, Groupe Hospitalier Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris and Université Paris Descartes, Paris 75015, France.
  • 12 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.
  • 13 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.
  • 14 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.
PMID: 26073779 DOI: 10.1016/j.ajhg.2015.05.004
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.

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