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Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects

Onoufriadis, Alexandros; Shoemark, Amelia; Schmidts, Miriam; Patel, Mitali; Jimenez, Gina; Liu, Hui; Thomas, Biju; Dixon, Melissa; Hirst, Robert A.; Rutman, Andrew; Burgoyne, Thomas; Williams, Christopher; Scully, Juliet; Bolard, Florence; Lafitte, Jean-Jacques; Beales, Philip L.; Hogg, Claire; Yang, Pinfen; Chung, Eddie M.K.; Emes, Richard D.; O'Callaghan, Christopher; Bouvagnet, Patrice; Mitchison, Hannah M.


Alexandros Onoufriadis

Amelia Shoemark

Miriam Schmidts

Mitali Patel

Gina Jimenez

Hui Liu

Biju Thomas

Melissa Dixon

Robert A. Hirst

Andrew Rutman

Thomas Burgoyne

Christopher Williams

Juliet Scully

Florence Bolard

Jean-Jacques Lafitte

Philip L. Beales

Claire Hogg

Pinfen Yang

Eddie M.K. Chung

Richard D. Emes

Christopher O'Callaghan

Patrice Bouvagnet

Hannah M. Mitchison


Primary ciliary dyskinesia (PCD) is an inherited chronic respiratory obstructive disease with randomized body laterality and infertility, resulting from cilia and sperm dysmotility. PCD is characterized by clinical variability and extensive genetic heterogeneity, associated with different cilia ultrastructural defects and mutations identified in >20 genes. Next generation sequencing (NGS) technologies therefore present a promising approach for genetic diagnosis which is not yet in routine use. We developed a targeted panel-based NGS pipeline to identify mutations by sequencing of selected candidate genes in 70 genetically undefined PCD patients. This detected loss-of-function RSPH1 mutations in four individuals with isolated central pair (CP) agenesis and normal body laterality, from two unrelated families. Ultrastructural analysis in RSPH1-mutated cilia revealed transposition of peripheral outer microtubules into the 'empty' CP space, accompanied by a distinctive intermittent loss of the central pair microtubules. We find that mutations in RSPH1, RSPH4A and RSPH9, which all encode homologs of components of the 'head' structure of ciliary radial spoke complexes identified in Chlamydomonas, cause clinical phenotypes that appear to be indistinguishable except at the gene level. By high-resolution immunofluorescence we identified a loss of RSPH4A and RSPH9 along with RSPH1 from RSPH1-mutated cilia, suggesting RSPH1 mutations may result in loss of the entire spoke head structure. CP loss is seen in up to 28% of PCD cases, in whom laterality determination specified by CP-less embryonic node cilia remains undisturbed. We propose this defect could arise from instability or agenesis of the ciliary central microtubules due to loss of their normal radial spoke head tethering.


Onoufriadis, A., Shoemark, A., Schmidts, M., Patel, M., Jimenez, G., Liu, H., …Mitchison, H. M. (2014). Targeted NGS gene panel identifies mutations in RSPH1 causing primary ciliary dyskinesia and a common mechanism for ciliary central pair agenesis due to radial spoke defects. Human Molecular Genetics, 23(13), 3362-3374.

Journal Article Type Article
Acceptance Date Jan 27, 2014
Online Publication Date Feb 11, 2014
Publication Date Jul 1, 2014
Deposit Date Jun 21, 2016
Publicly Available Date Jun 21, 2016
Journal Human Molecular Genetics
Print ISSN 0964-6906
Electronic ISSN 1460-2083
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 23
Issue 13
Pages 3362-3374
Public URL
Publisher URL


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