The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Lisbeth Tranebjærg, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. tranebjaerg@sund.ku.dk.
  • ,
  • Nicola Strenzke, Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University Medical Center, Göttingen, Germany.
  • ,
  • Sture Lindholm, ENT-Department, County Hospital Kalmar, Kalmar, Sweden.
  • ,
  • Nanna D Rendtorff, Department of Clinical Genetics, The Kennedy Center, Copenhagen University Hospital, Copenhagen, Denmark.
  • ,
  • Hanne Poulsen
  • Himanshu Khandelia, MEMPHYS – Center for Biomembrane Physics, Department of Physics and Chemistry, University of Southern Denmark, Odense
  • ,
  • Wojciech Kopec, Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • ,
  • Troels Johan Brünnich Lyngbye
  • ,
  • Christian Hamel, Département de radiothérapie oncologique/Inserm U1194, Institut du Cancer de Montpellier (ICM-Val d'Aurelle), Université de Montpellier, Montpellier, France.
  • ,
  • Cecile Delettre, Département de radiothérapie oncologique/Inserm U1194, Institut du Cancer de Montpellier (ICM-Val d'Aurelle), Université de Montpellier, Montpellier, France.
  • ,
  • Beatrice Bocquet, Département de radiothérapie oncologique/Inserm U1194, Institut du Cancer de Montpellier (ICM-Val d'Aurelle), Université de Montpellier, Montpellier, France.
  • ,
  • Michael Bille, Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet/Gentofte Hospital, Hellerup, Denmark.
  • ,
  • Hanne Højris Owen
  • ,
  • Toke Bek
  • Hanne Jensen, Eye Department Glostrup Hospital, Rigshospitalet, The Kennedy Centre, Glostrup, Denmark.
  • ,
  • Karen Østergaard
  • ,
  • Claes Möller, Audiological Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
  • ,
  • Linda Luxon, Department of Neurotology, National Hospital for Neurology, Queen Square, London, WC1N 3BG, UK.
  • ,
  • Lucinda Carr, Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • ,
  • Louise Wilson, North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • ,
  • Kaukab Rajput, Cochlear Implant Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • ,
  • Tony Sirimanna, Department of Audiovestibular Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH, UK.
  • ,
  • Katherine Harrop-Griffiths, Nuffield Hearing and Speech Centre, Royal National Throat Nose and Ear Hospital, London, WC1X 8DA, UK.
  • ,
  • Shamima Rahman, Genetic and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK.
  • ,
  • Barbara Vona, Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
  • ,
  • Julia Doll, Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
  • ,
  • Thomas Haaf, Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany.
  • ,
  • Oliver Bartsch, University Medical Centre, Institute of Human Genetics, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz, Germany.
  • ,
  • Hendrik Rosewich, Division of Pediatric Neurology, Department of Pediatric and Adolescent Medicine, University Medical Center, Göttingen, Germany.
  • ,
  • Tobias Moser, Institute for Auditory Neuroscience and InnerEarLab, University Medical Center, Göttingen, Germany.
  • ,
  • Maria Bitner-Glindzicz, Genetic and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK. maria.bitner@ucl.ac.uk.

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.

OriginalsprogEngelsk
TidsskriftHuman Genetics
Vol/bind137
Nummer2
Sider (fra-til)111-127
Antal sider17
ISSN0340-6717
DOI
StatusUdgivet - feb. 2018

Se relationer på Aarhus Universitet Citationsformater

ID: 121628705