Loss-of-function mutations in RSPH1 cause primary ciliary dyskinesia with central-complex and radial-spoke defects.

摘要: 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 this phenotype, diagnosis can be particularly difficult to establish, we combined homozygosity mapping and whole-exome sequencing consanguineous individual CC defects. This identified nonsense mutation RSPH1, gene ortholog Chlamydomonas reinhardtii encodes radial-spoke (RS)-head protein mainly expressed testis cells. Subsequent analyses RSPH1 biallelic mutations 10 48 independent families affected by These include splicing as demonstrated the study transcripts obtained airway cells individuals. Wild-type localizes within cilia cells, but were unable detect it an loss-of-function mutations. High-speed-videomicroscopy revealed coexistence different beating patterns—cilia normal beat frequency abnormal motion alongside immotile or slowed frequency—in each individual. shows that mutated 20.8% individuals could now improved screening. thus appear major etiology for PCD which fact includes RS thereby unveiling importance proper building CCs RSs humans.