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

Lisbeth Tranebjærg; Nicola Strenzke; Sture Lindholm; Nanna D. Rendtorff; Hanne Poulsen; Himanshu Khandelia; Wojciech Kopec; Troels J.Brünnich Lyngbye; Christian Hamel; Cecile Delettre; Beatrice Bocquet; Michael Bille; Hanne H. Owen; Toke Bek; Hanne Jensen; Karen Østergaard; Claes Möller; Linda Luxon; Lucinda Carr; Louise Wilson; Kaukab Rajput; Tony Sirimanna; Katherine Harrop-Griffiths; Shamima Rahman; Barbara Vona; Julia Doll; Thomas Haaf; Oliver Bartsch; Hendrik Rosewich; Tobias Moser; Maria Bitner-Glindzicz

doi:10.1007/s00439-017-1862-z

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

Lisbeth Tranebjærg^*, Nicola Strenzke, Sture Lindholm, Nanna D. Rendtorff, Hanne Poulsen, Himanshu Khandelia, Wojciech Kopec, Troels J.Brünnich Lyngbye, Christian Hamel, Cecile Delettre, Beatrice Bocquet, Michael Bille, Hanne H. Owen, Toke Bek, Hanne Jensen, Karen Østergaard, Claes Möller, Linda Luxon, Lucinda Carr, Louise WilsonKaukab Rajput, Tony Sirimanna, Katherine Harrop-Griffiths, Shamima Rahman, Barbara Vona, Julia Doll, Thomas Haaf, Oliver Bartsch, Hendrik Rosewich, Tobias Moser, Maria Bitner-Glindzicz

^*Corresponding author for this work

13 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Human Genetics
Volume	137
Issue number	2
Pages (from-to)	111-127
Number of pages	17
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-017-1862-z
Publication status	Published - 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s00439-017-1862-z

Cite this

Tranebjærg, L., Strenzke, N., Lindholm, S., Rendtorff, N. D., Poulsen, H., Khandelia, H., Kopec, W., Lyngbye, T. J. B., Hamel, C., Delettre, C., Bocquet, B., Bille, M., Owen, H. H., Bek, T., Jensen, H., Østergaard, K., Möller, C., Luxon, L., Carr, L., ... Bitner-Glindzicz, M. (2018). The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. Human Genetics, 137(2), 111-127. https://doi.org/10.1007/s00439-017-1862-z

Tranebjærg, L, Strenzke, N, Lindholm, S, Rendtorff, ND, Poulsen, H, Khandelia, H, Kopec, W, Lyngbye, TJB, Hamel, C, Delettre, C, Bocquet, B, Bille, M, Owen, HH, Bek, T, Jensen, H, Østergaard, K, Möller, C, Luxon, L, Carr, L, Wilson, L, Rajput, K, Sirimanna, T, Harrop-Griffiths, K, Rahman, S, Vona, B, Doll, J, Haaf, T, Bartsch, O, Rosewich, H, Moser, T & Bitner-Glindzicz, M 2018, 'The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management', Human Genetics, vol. 137, no. 2, pp. 111-127. https://doi.org/10.1007/s00439-017-1862-z

@article{7b6ec52431e24e2494a6b084c8eac9f9,

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

abstract = "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.",

author = "Lisbeth Tranebj{\ae}rg and Nicola Strenzke and Sture Lindholm and Rendtorff, {Nanna D.} and Hanne Poulsen and Himanshu Khandelia and Wojciech Kopec and Lyngbye, {Troels J.Br{\"u}nnich} and Christian Hamel and Cecile Delettre and Beatrice Bocquet and Michael Bille and Owen, {Hanne H.} and Toke Bek and Hanne Jensen and Karen {\O}stergaard and Claes M{\"o}ller and Linda Luxon and Lucinda Carr and Louise Wilson and Kaukab Rajput and Tony Sirimanna and Katherine Harrop-Griffiths and Shamima Rahman and Barbara Vona and Julia Doll and Thomas Haaf and Oliver Bartsch and Hendrik Rosewich and Tobias Moser and Maria Bitner-Glindzicz",

year = "2018",

doi = "10.1007/s00439-017-1862-z",

language = "English",

volume = "137",

pages = "111--127",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer",

number = "2",

}

TY - JOUR

T1 - The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management

AU - Tranebjærg, Lisbeth

AU - Strenzke, Nicola

AU - Lindholm, Sture

AU - Rendtorff, Nanna D.

AU - Poulsen, Hanne

AU - Khandelia, Himanshu

AU - Kopec, Wojciech

AU - Lyngbye, Troels J.Brünnich

AU - Hamel, Christian

AU - Delettre, Cecile

AU - Bocquet, Beatrice

AU - Bille, Michael

AU - Owen, Hanne H.

AU - Bek, Toke

AU - Jensen, Hanne

AU - Østergaard, Karen

AU - Möller, Claes

AU - Luxon, Linda

AU - Carr, Lucinda

AU - Wilson, Louise

AU - Rajput, Kaukab

AU - Sirimanna, Tony

AU - Harrop-Griffiths, Katherine

AU - Rahman, Shamima

AU - Vona, Barbara

AU - Doll, Julia

AU - Haaf, Thomas

AU - Bartsch, Oliver

AU - Rosewich, Hendrik

AU - Moser, Tobias

AU - Bitner-Glindzicz, Maria

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

UR - https://link.springer.com/article/10.1007%2Fs00439-018-1870-7

U2 - 10.1007/s00439-017-1862-z

DO - 10.1007/s00439-017-1862-z

M3 - Journal article

C2 - 29305691

AN - SCOPUS:85040046811

SN - 0340-6717

VL - 137

SP - 111

EP - 127

JO - Human Genetics

JF - Human Genetics

IS - 2

ER -

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

Abstract

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this