Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central-Complex and Radial-Spoke Defects
Esther Kott
(1, 2)
,
Marie Legendre
(2, 1)
,
Bruno Copin
(1, 2)
,
Jean-François Papon
(3, 4)
,
Florence Dastot-Le Moal
(1, 2)
,
Guy Montantin
(1, 2)
,
Philippe Duquesnoy
(1, 2)
,
William Piterboth
(1, 2)
,
Daniel Amram
(4)
,
Laurence Bassinet
(4)
,
Julie Beucher
(5)
,
Nicole Beydon
(2)
,
Eric Deneuville
(5)
,
Véronique Houdouin
(6)
,
Hubert Journel
(7)
,
Jocelyne Just
(2)
,
Nadia Nathan
(2)
,
Aline Tamalet
(2)
,
Nathalie Collot
(1, 2)
,
Ludovic Jeanson
(1, 2)
,
Morgane Le Gouez
(1, 2)
,
Benoit Vallette
(1, 2)
,
Anne-Marie Vojtek
(4)
,
Ralph Epaud
(4)
,
André Coste
(3, 4)
,
Annick Clement
(2)
,
Bruno Housset
(4)
,
Bruno Louis
(3)
,
Estelle Escudier
(1, 2)
,
Serge Amselem
(1, 2)
1
Physiopathologie des maladies génétiques d'expression pédiatrique
2 CHU Trousseau [APHP]
3 IMRB - Institut Mondor de Recherche Biomédicale
4 CHIC - Centre Hospitalier Intercommunal de Créteil
5 Centre Hospitalier Universitaire [Rennes]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
2 CHU Trousseau [APHP]
3 IMRB - Institut Mondor de Recherche Biomédicale
4 CHIC - Centre Hospitalier Intercommunal de Créteil
5 Centre Hospitalier Universitaire [Rennes]
6 AP-HP Hôpital universitaire Robert-Debré [Paris]
7 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
Esther Kott
- Fonction : co premier-auteur
Marie Legendre
- Fonction : co premier-auteur
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Bruno Copin
- Fonction : co premier-auteur
- PersonId : 1176543
- IdHAL : bruno-copin
Jean-François Papon
- Fonction : co premier-auteur
- PersonId : 890849
Florence Dastot-Le Moal
- Fonction : Auteur
- PersonId : 1182834
- IdHAL : florence-dastot-le-moal
- ORCID : 0000-0001-7368-5344
Guy Montantin
- Fonction : Auteur
- PersonId : 1195823
- IdHAL : guy-montantin
- ORCID : 0000-0003-1886-4133
William Piterboth
- Fonction : Auteur
- PersonId : 1175358
- IdHAL : williampiterboth
- ORCID : 0000-0002-0704-2428
Nadia Nathan
- Fonction : Auteur
- PersonId : 1029287
- IdHAL : nadianathan
- ORCID : 0000-0001-5149-7975
- IdRef : 081559410
Estelle Escudier
- Fonction : Auteur
- PersonId : 1213534
- IdHAL : estelle-escudier
- ORCID : 0000-0002-1569-8072
- IdRef : 033701997
Serge Amselem
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
Connectez-vous pour contacter l'auteur
Résumé
Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive respiratory disorder resulting from defects of motile cilia. Various axonemal ultrastructural phenotypes have been observed, including one with so-called central-complex (CC) defects, whose molecular basis remains unexplained in most cases. To identify genes involved in this phenotype, whose diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing in a consanguineous individual with CC defects. This identified a nonsense mutation in RSPH1, a gene whose ortholog in Chlamydomonas reinhardtii encodes a radial-spoke (RS)-head protein and is mainly expressed in respiratory and testis cells. Subsequent analyses of RSPH1 identified biallelic mutations in 10 of 48 independent families affected by CC defects. These mutations include splicing defects, as demonstrated by the study of RSPH1 transcripts obtained from airway cells of affected individuals. Wild-type RSPH1 localizes within cilia of airway cells, but we were unable to detect it in an individual with RSPH1 loss-of-function mutations. High-speed-videomicroscopy analyses revealed the coexistence of different ciliary beating patterns—cilia with a normal beat frequency but abnormal motion alongside immotile cilia or cilia with a slowed beat frequency—in each individual. This study shows that this gene is mutated in 20.8% of individuals with CC defects, whose diagnosis could now be improved by molecular screening. RSPH1 mutations thus appear as a major etiology for this PCD phenotype, which in fact includes RS defects, thereby unveiling the importance of RSPH1 in the proper building of CCs and RSs in humans.