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Shoemark, Amelia; Burgoyne, Thomas; Kwan, Robert; Dixon, Mellisa; Patel, Mitali P.; Rogers, Andrew V.; Onoufriadis, Alexandros; Scully, Juliet; Daudvohra, Farheen; Cullup, Thomas; Loebinger, Michael R.; Wilson, Robert; Chung, Eddie M.K.; Bush, Andrew; Mitchison, Hannah M.; Hogg, Claire

Primary ciliary dyskinesia with normal ultrastructure: three-dimensional tomography detects absence of DNAH11

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  • Medientyp: E-Artikel
  • Titel: Primary ciliary dyskinesia with normal ultrastructure: three-dimensional tomography detects absence of DNAH11
  • Beteiligte: Shoemark, Amelia; Burgoyne, Thomas; Kwan, Robert; Dixon, Mellisa; Patel, Mitali P.; Rogers, Andrew V.; Onoufriadis, Alexandros; Scully, Juliet; Daudvohra, Farheen; Cullup, Thomas; Loebinger, Michael R.; Wilson, Robert; Chung, Eddie M.K.; Bush, Andrew; Mitchison, Hannah M.; Hogg, Claire
  • Erschienen: European Respiratory Society (ERS), 2018
  • Erschienen in: European Respiratory Journal, 51 (2018) 2, Seite 1701809
  • Sprache: Englisch
  • DOI: 10.1183/13993003.01809-2017
  • ISSN: 1399-3003; 0903-1936
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p>In primary ciliary dyskinesia (PCD), motile ciliary dysfunction arises from ciliary defects usually confirmed by transmission electron microscopy (TEM). In 30% of patients, such as those with <jats:italic>DNAH11</jats:italic> mutations, apparently normal ultrastructure makes diagnosis difficult. Genetic analysis supports diagnosis, but may not identify definitive causal variants. Electron tomography, an extension of TEM, produces three-dimensional ultrastructural ciliary models with superior resolution to TEM. Our hypothesis is that tomography using existing patient samples will enable visualisation of <jats:italic>DNAH11-</jats:italic>associated ultrastructural defects. Dual axis tomograms from araldite-embedded nasal cilia were collected in 13 PCD patients with normal ultrastructure (<jats:italic>DNAH11</jats:italic> n=7, <jats:italic>HYDIN</jats:italic> n=2, <jats:italic>CCDC65</jats:italic> n=3 and <jats:italic>DRC1</jats:italic> n=1) and six healthy controls, then analysed using IMOD and Chimera software.</jats:p><jats:p>DNAH11 protein is localised to the proximal ciliary region. Within this region, electron tomography indicated a deficiency of &gt;25% of proximal outer dynein arm volume in all patients with <jats:italic>DNAH11</jats:italic> mutations (n=7) compared to other patients with PCD and normal ultrastructure (n=6) and healthy controls (n=6). <jats:italic>DNAH11</jats:italic> mutations cause a shared abnormality in ciliary ultrastructure previously undetectable by TEM. Advantageously, electron tomography can be used on existing diagnostic samples and establishes a structural abnormality where ultrastructural studies were previously normal.</jats:p>
  • Zugangsstatus: Freier Zugang