title: Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects.
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.
authors.affiliation: INSERM/UMR S933, Université Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Esther
authors.initials: E
authors.lastname: Kott
authors.forename: Marie
authors.initials: M
authors.lastname: Legendre
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Papon
authors.forename: Florence
authors.initials: F
authors.lastname: Dastot-Le Moal
authors.forename: Guy
authors.initials: G
authors.lastname: Montantin
authors.forename: Philippe
authors.initials: P
authors.lastname: Duquesnoy
authors.forename: William
authors.initials: W
authors.lastname: Piterboth
authors.forename: Daniel
authors.initials: D
authors.lastname: Amram
authors.forename: Laurence
authors.initials: L
authors.lastname: Bassinet
authors.forename: Julie
authors.initials: J
authors.lastname: Beucher
authors.forename: Nicole
authors.initials: N
authors.lastname: Beydon
authors.forename: Eric
authors.initials: E
authors.lastname: Deneuville
authors.forename: Véronique
authors.initials: V
authors.lastname: Houdouin
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Just
authors.forename: Nadia
authors.initials: N
authors.lastname: Nathan
authors.forename: Aline
authors.initials: A
authors.lastname: Tamalet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Collot
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jeanson
authors.forename: Morgane
authors.initials: M
authors.lastname: Le Gouez
authors.forename: Benoit
authors.initials: B
authors.lastname: Vallette
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Vojtek
authors.forename: Ralph
authors.initials: R
authors.lastname: Epaud
authors.forename: André
authors.initials: A
authors.lastname: Coste
authors.forename: Annick
authors.initials: A
authors.lastname: Clement
authors.forename: Bruno
authors.initials: B
authors.lastname: Housset
authors.forename: Bruno
authors.initials: B
authors.lastname: Louis
authors.forename: Estelle
authors.initials: E
authors.lastname: Escudier
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
mesh_terms: D000595:Amino Acid Sequence; D002923:Cilia / Q000235:genetics* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007619:Kartagener Syndrome / Q000235:genetics* / Q000473:pathology*; D008297:Male; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012119:Respiration
chemical_list: D004268:DNA-Binding Proteins; C484746:RSPH1 protein, human