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Mutations in Radial Spoke Head Protein Genes RSPH9 and RSPH4A Cause Primary Ciliary Dyskinesia with Central-Microtubular-Pair Abnormalities |
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| Authors: | Victoria H Castleman Leila Romio Rahul Chodhari Robert A Hirst Sandra CP de Castro Keith A Parker Patricia Ybot-Gonzalez Richard D Emes Stephen W Wilson Colin Wallis Colin A Johnson Rene J Herrera Andrew Rutman Mellisa Dixon Amelia Shoemark Andrew Bush Claire Hogg R Mark Gardiner Orit Reish Nicholas DE Greene Christopher O'Callaghan Saul Purton Eddie MK Chung and Hannah M Mitchison |
| Institution: | 1 General and Adolescent Paediatric Unit, University College London (UCL) Institute of Child Health, Rayne Building, 5 University Street, London WC1E 6JJ, UK 2 Nephro-Urology Unit, University College London (UCL) Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK 3 Division of Child Health, Department of Infection, Immunity, and Inflammation, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, UK 4 Neural Development Unit, University College London (UCL) Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK 5 Institute for Science and Technology in Medicine, School of Medicine, Keele University, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB, UK 6 Department of Cell and Development Biology, University College London, Gower Street, London WC1E 6BT, UK 7 Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK 8 Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK 9 Human Diversity Unit, Department of Molecular and Human Genetics, College of Medicine, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA 10 Department of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK 11 Genetics Institute, Assaf Harofeh Medical Center, Zerifin 70300 and the Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel 12 Algal Research Group, Institute of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK 13 Molecular Medicine Unit, University College London (UCL) Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK |
| 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. |
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