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J Biol Chem, Vol. 273, Issue 30, 18693-18696, July 24, 1998

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

Peter J. Kozel, Rick A. Friedman^§, Lawrence C. Erway^¶, Ebenezer N. Yamoah, Lynne H. Liu, Tara Riddle, John J. Duffy, Thomas Doetschman, Marian L. Miller^**, Emma Lou Cardell, and Gary E. Shull

From the Departments of  Molecular Genetics, Biochemistry and Microbiology,  Cell Biology and Anatomy, and ^** Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, the ^¶ Department of Biological Sciences, University of Cincinnati, Cincinnati, Ohio 45221, and the ^§ House Ear Institute, Los Angeles, California 90057

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.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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