Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

Mahmoud R. Fassad, Amelia Shoemark, Marie Legendre, Robert A. Hirst, France Koll, Pierrick le Borgne, Bruno Louis, Farheen Daudvohra, Mitali P. Patel, Lucie Thomas, Mellisa Dixon, Thomas Burgoyne, Joseph Hayes, Andrew G. Nicholson, Thomas Cullup, Lucy Jenkins, Siobhán B. Carr, Paul Aurora, Michel Lemullois, Anne Aubusson-Fleury & 6 others Jean-François Papon, Serge Amselem, Claire Hogg, Estelle Escudier, Anne-Marie Tassin, Hannah M. Mitchison

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Abstract

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

Original languageEnglish
Pages (from-to)984-994
Number of pages11
JournalAmerican Journal of Human Genetics
Volume103
Issue number6
Early online date21 Nov 2018
DOIs
Publication statusPublished - 6 Dec 2018

Fingerprint

Situs Inversus
Dyneins
Cilia
Mutation
Kartagener Syndrome
Mucociliary Clearance
Electron Microscope Tomography
Paramecium
Male Infertility
Body Fluids
Nose
Germ Cells
Respiratory Tract Infections
Respiratory System
Infertility
Chronic Disease

Keywords

  • DNAH9
  • dynein
  • motile cilia
  • mutation
  • primary ciliary dyskinesia
  • situs inversus
  • tomography

Cite this

Fassad, Mahmoud R. ; Shoemark, Amelia ; Legendre, Marie ; Hirst, Robert A. ; Koll, France ; le Borgne, Pierrick ; Louis, Bruno ; Daudvohra, Farheen ; Patel, Mitali P. ; Thomas, Lucie ; Dixon, Mellisa ; Burgoyne, Thomas ; Hayes, Joseph ; Nicholson, Andrew G. ; Cullup, Thomas ; Jenkins, Lucy ; Carr, Siobhán B. ; Aurora, Paul ; Lemullois, Michel ; Aubusson-Fleury, Anne ; Papon, Jean-François ; Amselem, Serge ; Hogg, Claire ; Escudier, Estelle ; Tassin, Anne-Marie ; Mitchison, Hannah M. / Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus. In: American Journal of Human Genetics. 2018 ; Vol. 103, No. 6. pp. 984-994.
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abstract = "Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.",
keywords = "DNAH9, dynein, motile cilia, mutation, primary ciliary dyskinesia, situs inversus, tomography",
author = "Fassad, {Mahmoud R.} and Amelia Shoemark and Marie Legendre and Hirst, {Robert A.} and France Koll and {le Borgne}, Pierrick and Bruno Louis and Farheen Daudvohra and Patel, {Mitali P.} and Lucie Thomas and Mellisa Dixon and Thomas Burgoyne and Joseph Hayes and Nicholson, {Andrew G.} and Thomas Cullup and Lucy Jenkins and Carr, {Siobh{\'a}n B.} and Paul Aurora and Michel Lemullois and Anne Aubusson-Fleury and Jean-Fran{\cc}ois Papon and Serge Amselem and Claire Hogg and Estelle Escudier and Anne-Marie Tassin and Mitchison, {Hannah M.}",
note = "Work by M. Legendre, S.A., and E.E. is supported by grants from the Fondation pour la Recherche M{\'e}dicale (DEQ20120323689) and the Legs Poix from the Chancellerie des Universit{\'e}s and from the Investissements d'Avenir (RaDiCo program; ANR-10-COHO-0003). Other funding for this study was provided by Action Medical Research (GN2101; H.M.M.) and Great Ormond Street Children’s Charity grant (V4515; H.M.M.) and Leadership awards (V1299, V2217; H.M.M.). We acknowledge support from the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. M.R.F. is supported by the British Council Newton-Mosharafa Fund and the Ministry of Higher Education, Egypt. Work by A.S. is independent research funded by a postdoctoral research fellowship from the National Institute of Health Research and Health Education England. The authors participate in the COST Action BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (BM1407) and this work was supported by two BM1407 COST Action STSM Grants awarded to M.R.F. and P.L.B.",
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Fassad, MR, Shoemark, A, Legendre, M, Hirst, RA, Koll, F, le Borgne, P, Louis, B, Daudvohra, F, Patel, MP, Thomas, L, Dixon, M, Burgoyne, T, Hayes, J, Nicholson, AG, Cullup, T, Jenkins, L, Carr, SB, Aurora, P, Lemullois, M, Aubusson-Fleury, A, Papon, J-F, Amselem, S, Hogg, C, Escudier, E, Tassin, A-M & Mitchison, HM 2018, 'Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus', American Journal of Human Genetics, vol. 103, no. 6, pp. 984-994. https://doi.org/10.1016/j.ajhg.2018.10.016

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus. / Fassad, Mahmoud R.; Shoemark, Amelia; Legendre, Marie; Hirst, Robert A.; Koll, France; le Borgne, Pierrick; Louis, Bruno; Daudvohra, Farheen; Patel, Mitali P.; Thomas, Lucie; Dixon, Mellisa; Burgoyne, Thomas; Hayes, Joseph; Nicholson, Andrew G.; Cullup, Thomas; Jenkins, Lucy; Carr, Siobhán B.; Aurora, Paul; Lemullois, Michel; Aubusson-Fleury, Anne; Papon, Jean-François; Amselem, Serge; Hogg, Claire; Escudier, Estelle; Tassin, Anne-Marie; Mitchison, Hannah M. (Lead / Corresponding author).

In: American Journal of Human Genetics, Vol. 103, No. 6, 06.12.2018, p. 984-994.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus

AU - Fassad, Mahmoud R.

AU - Shoemark, Amelia

AU - Legendre, Marie

AU - Hirst, Robert A.

AU - Koll, France

AU - le Borgne, Pierrick

AU - Louis, Bruno

AU - Daudvohra, Farheen

AU - Patel, Mitali P.

AU - Thomas, Lucie

AU - Dixon, Mellisa

AU - Burgoyne, Thomas

AU - Hayes, Joseph

AU - Nicholson, Andrew G.

AU - Cullup, Thomas

AU - Jenkins, Lucy

AU - Carr, Siobhán B.

AU - Aurora, Paul

AU - Lemullois, Michel

AU - Aubusson-Fleury, Anne

AU - Papon, Jean-François

AU - Amselem, Serge

AU - Hogg, Claire

AU - Escudier, Estelle

AU - Tassin, Anne-Marie

AU - Mitchison, Hannah M.

N1 - Work by M. Legendre, S.A., and E.E. is supported by grants from the Fondation pour la Recherche Médicale (DEQ20120323689) and the Legs Poix from the Chancellerie des Universités and from the Investissements d'Avenir (RaDiCo program; ANR-10-COHO-0003). Other funding for this study was provided by Action Medical Research (GN2101; H.M.M.) and Great Ormond Street Children’s Charity grant (V4515; H.M.M.) and Leadership awards (V1299, V2217; H.M.M.). We acknowledge support from the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. M.R.F. is supported by the British Council Newton-Mosharafa Fund and the Ministry of Higher Education, Egypt. Work by A.S. is independent research funded by a postdoctoral research fellowship from the National Institute of Health Research and Health Education England. The authors participate in the COST Action BEAT-PCD: Better Evidence to Advance Therapeutic options for PCD network (BM1407) and this work was supported by two BM1407 COST Action STSM Grants awarded to M.R.F. and P.L.B.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

AB - Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

KW - DNAH9

KW - dynein

KW - motile cilia

KW - mutation

KW - primary ciliary dyskinesia

KW - situs inversus

KW - tomography

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DO - 10.1016/j.ajhg.2018.10.016

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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