A mutation in<i>ATP11A</i>causes autosomal-dominant auditory neuropathy type 2

Chepurwar, Shashank; Loh, Sarah M von; Wigger, Daniela; Neef, Jakob; Frommolt, Peter; Beutner, Dirk; Lang‐Roth, Ruth; Kubisch, Christian; Strenzke, Nicola; Volk, Alexander E

doi:10.1093/hmg/ddac267

Cited by 5 publications

(3 citation statements)

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“…Over 250 genes are related to syndromic and nonsyndromic hearing loss [ 3 ]. Recently, ATP11A was reported as the gene related to DFNA33, a form of bilateral sensorineural hearing loss found in three Caucasian families [ 4 , 5 ]. ATP8A2 is also required for normal visual and auditory function, while its mutation impedes the survival of photoreceptor and spiral ganglion neurons [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

Xing

Peng

et al. 2023

Cell Mol Biol Lett

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Background Phosphatidylserine is translocated to the inner leaflet of the phospholipid bilayer membrane by the flippase function of type IV P-tape ATPase (P4-ATPase), which is critical to maintain cellular stability and homeostasis. Transmembrane protein 30A (TMEM30A) is the β-subunit of P4-ATPase. Loss of P4-ATPase function causes sensorineural hearing loss and visual dysfunction in human. However, the function of TMEM30A in the auditory system is unclear. Methods P4-ATPase subtype expression in the cochlea was detected by immunofluorescence staining and quantitative real-time polymerase chain reaction (qRT-PCR) at different developmental stages. Hair cell specific TMEM30A knockout mice and wild-type littermates were used for the following functional and morphological analysis. Auditory function was evaluated by auditory brainstem response. We investigated hair cell and stereocilia morphological changes by immunofluorescence staining. Scanning electron microscopy was applied to observe the stereocilia ultrastructure. Differentially expressed transcriptomes were analyzed based on RNA-sequencing data from knockout and wild-type mouse cochleae. Differentially expressed genes were verified by qRT-PCR. Results TMEM30A and subtypes of P4-ATPase are expressed in the mouse cochlea in a temporal-dependent pattern. Deletion of TMEM30A in hair cells impaired hearing onset due to progressive hair cell loss. The disrupted kinocilia placement and irregular distribution of spectrin-α in cuticular plate indicated the hair cell planar polarity disruption in TMEM30A deletion hair cells. Hair cell degeneration begins at P7 and finishes around P14. Transcriptional analysis indicates that the focal adhesion pathway and stereocilium tip-related genes changed dramatically. Without the TMEM30A chaperone, excessive ATP8A2 accumulated in the cytoplasm, leading to overwhelming endoplasmic reticulum stress, which eventually contributed to hair cell death. Conclusions Deletion of TMEM30A led to disrupted planar polarity and stereocilia bundles, and finally led to hair cell loss and auditory dysfunction. TMEM30A is essential for hair cell polarity maintenance and membrane homeostasis. Our study highlights a pivotal role of TMEM30A in the postnatal development of hair cells and reveals the possible mechanisms underlying P4-ATPase-related genetic hearing loss.

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Section: Introductionmentioning

confidence: 99%

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

Xing

Peng

et al. 2023

Cell Mol Biol Lett

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“…Among the remaining loci with an unknown causal gene is DFNA33 that was published in 2009 through the ascertainment of a large, multi-generational German family, segregating progressive sensorineural non-syndromic hearing loss with a variable post-lingual onset ( Bönsch et al, 2009 ). This brief research report describes follow-up genome sequencing analysis in light of the recent discovery of ATP11A , a gene that is responsible for autosomal dominant non-syndromic hearing loss (DFNA84) ( Pater et al, 2022 ) and auditory neuropathy (AUNA2) ( Chepurwar et al, 2022 ), which coincidentally also overlaps with the DFNA33 genomic coordinates at chr13q34.…”

Section: Introductionmentioning

confidence: 99%

Unraveling haplotype errors in the DFNA33 locus

Vona,

Regele,

Rad

et al. 2023

Front. Genet.

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Genetic heterogeneity makes it difficult to identify the causal genes for hearing loss. Studies from previous decades have mapped numerous genetic loci, providing critical supporting evidence for gene discovery studies. Despite widespread sequencing accessibility, many historically mapped loci remain without a causal gene. The DFNA33 locus was mapped in 2009 and coincidentally contains ATP11A, a gene recently associated with autosomal dominant hearing loss and auditory neuropathy type 2. In a rare opportunity, we genome-sequenced a member of the original family to determine whether the DFNA33 locus may also be assigned to ATP11A. We identified a deep intronic variant in ATP11A that showed evidence of functionally normal splicing. Furthermore, we re-assessed haplotypes from the originally published DFNA33 family and identified two double recombination events and one triple recombination event in the pedigree, a highly unlikely occurrence, especially at this scale. This brief research report also serves as a call to the community to revisit families who have previously been involved in gene mapping studies, provide closure, and resolve these historical loci.

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“…precipitation(Scholl et al, 2014) OHCs -basolateral membrane, adult mice(Rüttiger et al, 2004) Anti-Synapsin1/2(1:400) Synthetic peptide from rat Synapsin1 (a.a. 2-28) Sysy* -guinea pig polyclonal 106-004, Lot# 1-25 RRID: AB_1106784 Validated by immunoblot / Western blot by Sysy* using Synapsin KO mouse tissue lysates Olivocochlear efferent terminals(Hua et al, 2021;Chepurwar et al, 2023) Sysy*, Synaptic Systems; DSHB**, Developmental Studies Hybridoma Bank.…”

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Age-related alterations in efferent medial olivocochlear-outer hair cell and primary auditory ribbon synapses in CBA/J mice

Dörje,

Shvachiy,

Kück

et al. 2024

Front. Cell. Neurosci.

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IntroductionHearing decline stands as the most prevalent single sensory deficit associated with the aging process. Giving compelling evidence suggesting a protective effect associated with the efferent auditory system, the goal of our study was to characterize the age-related changes in the number of efferent medial olivocochlear (MOC) synapses regulating outer hair cell (OHC) activity compared with the number of afferent inner hair cell ribbon synapses in CBA/J mice over their lifespan.MethodsOrgans of Corti of 3-month-old CBA/J mice were compared with mice aged between 10 and 20 months, grouped at 2-month intervals. For each animal, one ear was used to characterize the synapses between the efferent MOC fibers and the outer hair cells (OHCs), while the contralateral ear was used to analyze the ribbon synapses between inner hair cells (IHCs) and type I afferent nerve fibers of spiral ganglion neurons (SGNs). Each cochlea was separated in apical, middle, and basal turns, respectively.ResultsThe first significant age-related decline in afferent IHC-SGN ribbon synapses was observed in the basal cochlear turn at 14 months, the middle turn at 16 months, and the apical turn at 18 months of age. In contrast, efferent MOC-OHC synapses in CBA/J mice exhibited a less pronounced loss due to aging which only became significant in the basal and middle turns of the cochlea by 20 months of age.DiscussionThis study illustrates an age-related reduction on efferent MOC innervation of OHCs in CBA/J mice starting at 20 months of age. Our findings indicate that the morphological decline of efferent MOC-OHC synapses due to aging occurs notably later than the decline observed in afferent IHC-SGN ribbon synapses.

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A mutation inATP11Acauses autosomal-dominant auditory neuropathy type 2

Cited by 5 publications

References 31 publications

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

TMEM30A is essential for hair cell polarity maintenance in postnatal mouse cochlea

Unraveling haplotype errors in the DFNA33 locus

Age-related alterations in efferent medial olivocochlear-outer hair cell and primary auditory ribbon synapses in CBA/J mice

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