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 1

Missense mutation in the Cyba gene of the nmf333 mouse strain.

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Missense mutation in the Cyba gene of the nmf333 mouse strain. ...
(A) The p22phox-encoding Cyba gene is located near the distal telomere of mouse chromosome 8 (top ideogram). Cyba contains 6 exons (numbered black boxes). A deoxythymidine nucleotide (T) in exon 5 of WT Cyba (upper chromatogram) is replaced by a deoxycytosine (C) in the nmf333 mutant strain, as indicated by an arrow in the lower chromatogram. The point mutation changed the 121st amino acid of p22phox from tyrosine (Tyr) to histidine (His), as shown in the translation lines. (B) The tyrosine to histidine amino acid substitution (Y121H) is localized to the second predicted transmembrane helix of p22phox. (C) Genotyping for the nmf333 mutation with PCR amplification and subsequent BslI digestion of a fragment of the Cyba gene. Lanes show a 100-bp ladder and the genotyping results using DNA samples from WT, heterozygous nmf333 (nmf333/+), and homozygous nmf333 (nmf333/nmf333) mice. Fragment sizes are given in bp.