Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
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.
Castleman
Victoria H
VH
General and Adolescent Paediatric Unit, University College London Institute of Child Health, Rayne Building, 5 University Street, London WC1E 6JJ, UK.
Romio
Leila
L
Chodhari
Rahul
R
Hirst
Robert A
RA
de Castro
Sandra C P
SC
Parker
Keith A
KA
Ybot-Gonzalez
Patricia
P
Emes
Richard D
RD
Wilson
Stephen W
SW
Wallis
Colin
C
Johnson
Colin A
CA
Herrera
Rene J
RJ
Rutman
Andrew
A
Dixon
Mellisa
M
Shoemark
Amelia
A
Bush
Andrew
A
Hogg
Claire
C
Gardiner
R Mark
RM
Reish
Orit
O
Greene
Nicholas D E
ND
O'Callaghan
Christopher
C
Purton
Saul
S
Chung
Eddie M K
EM
Mitchison
Hannah M
HM
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
D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C484746:RSPH1 protein, human; C573132:RSPH9 protein, human