International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 72 - THE NOX3 AND NOXO1 GENES, ENCODING PRESUMPTIVE MEMBERS OF AN NADPH OXIDASE COMPLEX, ARE REQUIRED FOR NORMAL VESTIBULAR FUNCTION AND DEVELOPMENT

Bergstrom DE 1, Bergstrom RA 1, Munroe RJ 2, Schimenti JC 2, Gagnon LH 1, Johnson KR 1, Heinzmann U 3, Stumm G 4, Paffenholz R 4

1 The Jackson Laboratory, Bar Harbor, United States, 2 Cornell University, Ithaca, United States, 3 GSF-National Research Center for Environmental Health, Neuherberg, Germany, 4 Ingenium Pharmaceuticals, Martinsried, Germany

The mammalian inner ear consists of the cochlea (required for auditory sensation) and the vestibular system (required for balance sensation). The vestibular system is comprised of the three semicircular canals that detect angular acceleration, plus the saccule and utricle and their associated maculae that detect linear acceleration.

The head tilt (het) and head slant (hslt) loci of mice are required for the normal development and function of the vestibular system. Head tilt and head slant mutant mice display a complete absence of saccular and utricular otoconia, calcium-containing crystals that act as inertial masses affixed to the maculae. Mutant mice that lack these otoconia display several behaviors consistent with vestibular impairment including circling, an abnormal tilting posture, impaired righting reflexes, and inability to swim.

Recombination- and deletion-based positional cloning strategies have identified Nox3 and Noxo1 as the causative genes underlying the het and hslt phenotypes, respectively. Sequence analysis shows that Nox3 is paralogous to gp91phox (Nox2), an NADPH oxidase of immune cells that generates reactive oxygen species as a bacteriocidal weapon against invading microorganisms. Similarly, Noxo1 is paralogous to p47phox (Ncf1), a cytosolic component of the same oxidase complex.

Based on these results, we have hypothesized that a novel NADPH oxidase complex, composed of immune complex paralogs, is present in the vestibular system and acts to initiate otoconial development from components in the endolymph including otoconin 90, Ca2+, otopetrin 1, and HCO3-.

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