Titel: Mutations in ATP11A cause autosomal-dominant auditory synaptopathy/neuropathy
ID: W9-002
Art: Invited talk
Redezeit: 15 min
Session: Workshop 9
Monogenic Syndromes

Referent: Alexander E. Volk (Hamburg/DE)

Abstract - Text


Auditory synaptopathy/neuropathy (AS/AN) is a specific type of sensorineural hearing loss characterized by sustained cochlear outer hair cell function but abnormal auditory brainstem responses. It is a heterogeneous disorder, which may be caused by genetic or environmental factors (like postnatal hyperbilirubinemia). The genetic forms are subdivided into syndromic and non-syndromic types, and show different inheritance patterns. In 2017, we published a large family with autosomal-dominant AS/AN and identified regions on chromosomal bands 12q24 or 13q34 as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2).

By whole genome sequencing we now detected a 5500bp deletion on chromosome 13q34. The deletion affects both isoforms of ATP11A and leads to the use of an alternative last exon. ATP11A encodes a P-type ATPase which translocates phospholipids from exoplasmic to the cytoplasmic leaflet of the plasma membranes. Overexpression of ATP11A carrying the altered C-terminal end, revealed correct CDC50A-dependent subcellular localization. By a flippase activity assay we could however detect a reduced translocation of phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and  in the cochlear nucleus in mice. Conditional Atp11a knockout mice, show a progressive reduction or de-synchronization of action potential generation in spiral ganglion neurons starting by the age of 10 weeks, recapitulating the human phenotye of auditory synaptopathy/neuropathy.

By applying whole genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could identifiy mutations of ATP11A as the genetic cause of AUNA2.