title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous inherited disorder arising from dysmotility of motile cilia and sperm. This is associated with a variety of ultrastructural defects of the cilia and sperm axoneme that affect movement, leading to clinical consequences on respiratory-tract mucociliary clearance and lung function, fertility, and left-right body-axis determination. We performed whole-genome SNP-based linkage analysis in seven consanguineous families with PCD and central-microtubular-pair abnormalities. This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0). Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head. In situ hybridization of murine Rsph9 shows gene expression restricted to regions containing motile cilia. Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile, "9+2"-structure cilia and flagella. This effect is rescued by reintroduction of gene expression for restoration of a normal beat pattern in zebrafish. Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.
authors.affiliation: General and Adolescent Paediatric Unit, University College London Institute of Child Health, Rayne Building, 5 University Street, London WC1E 6JJ, UK.
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Castleman
authors.forename: Leila
authors.initials: L
authors.lastname: Romio
authors.forename: Rahul
authors.initials: R
authors.lastname: Chodhari
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hirst
authors.forename: Sandra C P
authors.initials: SC
authors.lastname: de Castro
authors.forename: Keith A
authors.initials: KA
authors.lastname: Parker
authors.forename: Patricia
authors.initials: P
authors.lastname: Ybot-Gonzalez
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wilson
authors.forename: Colin
authors.initials: C
authors.lastname: Wallis
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Rene J
authors.initials: RJ
authors.lastname: Herrera
authors.forename: Andrew
authors.initials: A
authors.lastname: Rutman
authors.forename: Mellisa
authors.initials: M
authors.lastname: Dixon
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.forename: Claire
authors.initials: C
authors.lastname: Hogg
authors.forename: R Mark
authors.initials: RM
authors.lastname: Gardiner
authors.forename: Orit
authors.initials: O
authors.lastname: Reish
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.forename: Christopher
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Saul
authors.initials: S
authors.lastname: Purton
authors.forename: Eddie M K
authors.initials: EM
authors.lastname: Chung
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
mesh_terms: D000818:Animals; D002696:Chlamydomonas / Q000235:genetics; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D002923:Cilia / Q000235:genetics / Q000473:pathology*; D000013:Congenital Abnormalities / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D007619:Kartagener Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015027:Zebrafish / Q000235:genetics
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C484746:RSPH1 protein, human; C573132:RSPH9 protein, human