A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2

2022 | journal article. A publication with affiliation to the University of Göttingen.

Jump to:Cite & Linked | Documents & Media | Details | Version history

Cite this publication

​Chepurwar, Shashank, Sarah M. von Loh, Daniela C. Wigger, Jakob Neef, Peter Frommolt, Dirk Beutner, Ruth Lang-Roth, Christian Kubisch, Nicola Strenzke, and Alexander E. Volk. "A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2​." ​Human Molecular Genetics (2022): ​ddac267​. ​https://doi.org/10.1093/hmg/ddac267.

Documents & Media

License

Published Version

GRO License GRO License

Details

Authors
Chepurwar, Shashank; Loh, Sarah M. von; Wigger, Daniela C.; Neef, Jakob ; Frommolt, Peter; Beutner, Dirk ; Lang-Roth, Ruth; Kubisch, Christian; Strenzke, Nicola ; Volk, Alexander E.
Abstract
Auditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted due to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of auditory neuropathy. By combining whole genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2.
Issue Date
2022
Journal
Human Molecular Genetics 
Project
SFB 889: Zelluläre Mechanismen sensorischer Verarbeitung 
Organization
Universitätsmedizin Göttingen ; Institut für Auditorische Neurowissenschaften ; Klinik für Hals-Nasen-Ohrenheilkunde 
ISSN
0964-6906
eISSN
1460-2083
Language
English

Reference

Citations


Social Media