Article open access publication

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

Human Genetics, Springer Nature, ISSN 0340-6717

Volume 137, 2, 2018

DOI:10.1007/s00439-017-1862-z, Dimensions: pub.1100192338, PMID: 29305691,



  1. (1) Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet/Bispebjerg, Copenhagen, Denmark
  2. (2) University of Copenhagen, grid.5254.6, KU
  3. (3) Department of Clinical Genetics, The Kennedy Center, Copenhagen University Hospital, Copenhagen, Denmark
  4. (4) University Medical Center Göttingen, grid.411984.1
  5. (5) ENT-Department, County Hospital Kalmar, Kalmar, Sweden
  6. (6) Aarhus University, grid.7048.b, AU
  7. (7) University of Southern Denmark, grid.10825.3e, SDU
  8. (8) Max Planck Institute for Biophysical Chemistry, grid.418140.8
  9. (9) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  10. (10) Institute for Neurosciences of Montpellier, grid.464046.4
  11. (11) University of Montpellier, grid.121334.6
  12. (12) University Hospital of Montpellier, grid.157868.5
  13. (13) Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet/Gentofte Hospital, Hellerup, Denmark
  14. (14) Rigshospitalet, grid.475435.4, Capital Region
  15. (15) Örebro University, grid.15895.30
  16. (16) National Hospital for Neurology and Neurosurgery, grid.436283.8
  17. (17) Great Ormond Street Hospital for Children NHS Foundation Trust, grid.424537.3
  18. (18) Royal National Throat Nose and Ear Hospital, grid.439342.b
  19. (19) University College London, grid.83440.3b
  20. (20) University of Würzburg, grid.8379.5
  21. (21) University Medical Centre, Institute of Human Genetics, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz, Germany


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.

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Times Cited: 14

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