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Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects. 2013
Esther Kott, and
Marie Legendre, and
Bruno Copin, and
Jean-François Papon, and
Florence Dastot-Le Moal, and
Guy Montantin, and
Philippe Duquesnoy, and
William Piterboth, and
Daniel Amram, and
Laurence Bassinet, and
Julie Beucher, and
Nicole Beydon, and
Eric Deneuville, and
Véronique Houdouin, and
Hubert Journel, and
Jocelyne Just, and
Nadia Nathan, and
Aline Tamalet, and
Nathalie Collot, and
Ludovic Jeanson, and
Morgane Le Gouez, and
Benoit Vallette, and
Anne-Marie Vojtek, and
Ralph Epaud, and
André Coste, and
Annick Clement, and
Bruno Housset, and
Bruno Louis, and
Estelle Escudier, and
Serge Amselem
INSERM/UMR S933, Université Pierre et Marie Curie-Paris 6, Paris, France.
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.
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