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
(6)
,
Eric Deneuville
(5)
,
Véronique Houdouin
(7)
,
Hubert Journel
(8)
,
Jocelyne Just
(9)
,
Nadia Nathan
(10)
,
Aline Tamalet
(10)
,
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
(10)
,
Bruno Housset
(4)
,
Bruno Louis
(3)
,
Estelle Escudier
(1, 2)
,
Serge Amselem
(1, 2)
1
Physiopathologie des maladies génétiques d'expression pédiatrique
2 Service de génétique et embryologie médicales [CHU Trousseau]
3 IMRB - Institut Mondor de Recherche Biomédicale
4 CHIC - Centre Hospitalier Intercommunal de Créteil
5 Centre Hospitalier Universitaire [Rennes]
6 Service de physiologie, unité fonctionnelle d’explorations respiratoires [CHU Trousseau]
7 AP-HP Hôpital universitaire Robert-Debré [Paris]
8 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
9 Centre de l'Asthme et des Allergies [CHU Trousseau]
10 Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau]
2 Service de génétique et embryologie médicales [CHU Trousseau]
3 IMRB - Institut Mondor de Recherche Biomédicale
4 CHIC - Centre Hospitalier Intercommunal de Créteil
5 Centre Hospitalier Universitaire [Rennes]
6 Service de physiologie, unité fonctionnelle d’explorations respiratoires [CHU Trousseau]
7 AP-HP Hôpital universitaire Robert-Debré [Paris]
8 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
9 Centre de l'Asthme et des Allergies [CHU Trousseau]
10 Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau]
Esther Kott
- Function : relator_co_first_author
Marie Legendre
- Function : relator_co_first_author
Bruno Copin
- Function : relator_co_first_author
Jean-François Papon
- Function : relator_co_first_author
Serge Amselem
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
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Abstract
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.