Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice
Yoko Nakano, … , Sherri M. Jones, Botond Bánfi
Yoko Nakano, … , Sherri M. Jones, Botond Bánfi
Published February 21, 2008
Citation Information: J Clin Invest. 2008;118(3):1176-1185. https://doi.org/10.1172/JCI33835.
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Mutation of the Cyba gene encoding p22phox causes vestibular and immune defects in mice

Abstract

In humans, hereditary inactivation of either p22phox or gp91phox leads to chronic granulomatous disease (CGD), a severe immune disorder characterized by the inability of phagocytes to produce bacteria-destroying ROS. Heterodimers of p22phox and gp91phox proteins constitute the superoxide-producing cytochrome core of the phagocyte NADPH oxidase. In this study, we identified the nmf333 mouse strain as what we believe to be the first animal model of p22phox deficiency. Characterization of nmf333 mice revealed that deletion of p22phox inactivated not only the phagocyte NADPH oxidase, but also a second cytochrome in the inner ear epithelium. As a consequence, mice of the nmf333 strain exhibit a compound phenotype consisting of both a CGD-like immune defect and a balance disorder caused by the aberrant development of gravity-sensing organs. Thus, in addition to identifying a model of p22phox-dependent immune deficiency, our study indicates that a clinically identifiable patient population with an otherwise cryptic loss of gravity-sensor function may exist. Thus, p22phox represents a shared and essential component of at least 2 superoxide-producing cytochromes with entirely different biological functions. The site of p22phox expression in the inner ear leads us to propose what we believe to be a novel mechanism for the control of vestibular organogenesis.

Authors

Yoko Nakano, Chantal M. Longo-Guess, David E. Bergstrom, William M. Nauseef, Sherri M. Jones, Botond Bánfi

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Figure 7

The Cyba transgene rescues the balance disorder characteristic of the nmf333 strain.

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The Cyba transgene rescues the balance disorder characteristic of the nm...
(A) Immunostaining of the endolymphatic duct (asterisk) of an embryo from a Cyba-transgenic homozygous nmf333 mouse and from a homozygous nmf333 mouse at E15 using an anti-p22phox antibody. Left: localization of the red immunofluorescence signal (p22phox). Right: superimposition of the fluorescence signal and the differential interference contrast image (merged). SC, semicircular canal lumen. Scale bars: 20 μm. (B) Von Kossa staining of calcium salts in the saccule of a Cyba-transgenic homozygous nmf333 mouse (arrow indicates otoconia). n = 3. Scale bar: 100 μm. (C) The Cyba transgene restored the ability of nmf333 mice to orient themselves in water as demonstrated by the swimming test. (D) Time spent on fixed-speed rotarod (10 rpm) before falling by WT, homozygous nmf333, and Cyba-transgenic homozygous nmf333 mice during 3 assays over 3 days (d1, d2, d3). The maximum duration of the test was 180 s (horizontal line; n = 5 per group). P < 0.0001 for the genotype variable and P = 0.0042 for the time variable, 2-way ANOVA; **P < 0.01, ***P < 0.001, post-hoc Bonferroni test. (E) The Cyba transgene restores the VsEP threshold in mice homozygous for nmf333. Individual VsEP thresholds are shown for nmf333/333 (filled squares, n = 4) and Cyba-transgenic homozygous nmf333 (filled circles, n = 7) mice. Mean thresholds are indicated by solid horizontal lines ± 1 SD (dashed lines). ***P < 0.0001; 1-tailed t test against the theoretically possible lowest threshold in the nmf333 group (6 dB re 1.0 g/ms).