Title

CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear.

Document Type

Article

Publication Date

9-15-2021

Publication Title

Hearing research

Keywords

JMG

JAX Source

Hear Res 2021 Sep 15; 409:108327

Volume

409

First Page

108327

Last Page

108327

ISSN

1878-5891

PMID

34388681

DOI

https://doi.org/10.1016/j.heares.2021.108327

Grant

DC004301, CA034196

Abstract

CACHD1 recently was shown to be an α2δ-like subunit that can modulate the activity of some types of voltage-gated calcium channels, including the low-voltage activated, T-type CaV3 channels. CACHD1 is widely expressed in the central nervous system but its biological functions and relationship to disease states are unknown. Here, we report that mice with deleterious Cachd1 mutations are hearing impaired and have balance defects, demonstrating that CACHD1 is functionally important in the peripheral auditory and vestibular organs of the inner ear. The vestibular dysfunction of Cachd1 mutant mice, exhibited by leaning and head tilting behaviors, is related to a deficiency of calcium carbonate crystals (otoconia) in the saccule and utricle. The auditory dysfunction, shown by ABR threshold elevations and reduced DPOAEs, is associated with reduced endocochlear potentials and increased endolymph calcium concentrations. Paint-fills of mutant inner ears from prenatal and newborn mice revealed dilation of the membranous labyrinth caused by an enlarged volume of endolymph. These pathologies all can be related to a disturbance of calcium homeostasis in the endolymph of the inner ear, presumably caused by the loss of CACHD1 regulatory effects on voltage-gated calcium channel activity. Cachd1 expression in the cochlea appears stronger in late embryonic stages than in adults, suggesting an early role in establishing endolymph calcium concentrations. Our findings provide new insights into CACHD1 function and suggest the involvement of voltage-gated calcium channels in endolymph homeostasis, essential for normal auditory and vestibular function.

Comments

We thank Chantal Longo-Guess for ABR tests of linkage cross mice, Sandra Gray for mouse husbandry, and the shared services of The Jackson Laboratory for whole ex- ome sequencing, generation of mice with CRISPR-Cas9 mutations, and strain cryopreservation.

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