BALANCE AND HEARING DEFICITS IN MICE WITH A NULL MUTATION IN THE GENEENCODING PLASMA-MEMBRANE CA2-ATPASE ISOFORM-2()

Plasma membrane Ca2+-ATPase isoform 2 (PMCA2) exhibits a highly restri cted tissue distribution, suggesting that it serves more specialized p hysiological functions than some of the other isoforms, A unique role in hearing is indicated by the high levels of PMCA2 expression in coch lear outer hair cells and spiral ganglion cells. To analyze the physio logical role of PMCA2 we used gene targeting to produce PMCA2-deficien t mice, Breeding of heterozygous mice yielded live homozygous mutant o ffspring. 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 mut ant and wild-type mice revealed that null mutants had slightly increas ed numbers of Purkinje neurons tin 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 C orti. Analysis of auditory evoked brainstem responses revealed that ho mozygous mutants were deaf and that heterozygous mice had a significan t 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.