Balance and Hearing Deficits in Mice with a Null Mutation in the Gene Encoding Plasma Membrane Ca2+-ATPase Isoform 2

TLDR

PMCA2 is a highly restricted plasma membrane Ca²⁺‑ATPase whose high expression in cochlear outer hair cells and spiral ganglion cells indicates a specialized role in hearing. The study aimed to determine PMCA2’s physiological function by generating PMCA2‑deficient mice through gene targeting. Gene targeting produced PMCA2‑null mice, and breeding of heterozygous animals yielded live homozygous mutants for analysis. PMCA2‑null mice show growth retardation, ataxia, balance deficits, increased Purkinje cells, a thinner cerebellar molecular layer, absent otoconia, cochlear abnormalities, and deafness, while heterozygotes have significant hearing loss, proving that PMCA2 is essential for balance and hearing and likely supplies calcium for otoconia formation.

Abstract

Plasma membrane Ca²⁺-ATPase isoform 2 (PMCA2) exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiological functions than some of the other isoforms. A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice. Breeding of heterozygous mice yielded live homozygous mutant offspring. PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance. Histological analysis of the cerebellum and inner ear of mutant and wild-type mice revealed that null mutants had slightly increased numbers of Purkinje neurons (in which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory evoked brainstem responses revealed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrate that PMCA2 is required for both balance and hearing and suggest that it may be a major source of the calcium used in the formation and maintenance of otoconia.