RGD Reference Report - Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba).

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Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba).
Authors:	Mori, M Li, G Hashimoto, M Nishio, A Tomozawa, H Suzuki, N Usami, S Higuchi, K Matsumoto, K
Citation:	Mori M, etal., J Leukoc Biol. 2009 Sep;86(3):473-8. doi: 10.1189/jlb.1108715. Epub 2009 Apr 30.
RGD ID:	11040542
Pubmed:	PMID:19406829 (View Abstract at PubMed)
DOI:	DOI:10.1189/jlb.1108715 (Journal Full-text)
MES is a rat strain that spontaneously develops severe blood eosinophilia as a hereditary trait. Herein, we report that eosinophilia in MES rats is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba; also known as p22(phox)), which is an essential component of the superoxide-generating NADPH oxidase complex. The MES rat has a deletion of four nucleotides, including the 5' splice donor GpT of intron 4 of the Cyba gene. As a consequence of the deletion, a 51-nucleotide sequence of intron 4 is incorporated into the Cyba transcripts. Leukocytes from the MES strain lack both CYBA protein and NADPH oxidase activity. Nevertheless, unlike patients with chronic granulomatous disease, who suffer from infections with pathogens due to similar genetic defects in NADPH oxidase, MES rats retain normal innate immune defense against Staphylococcus aureus infection. This is due to large quantities of peritoneal eosinophils in MES rats, which phagocytose and kill the bacteria. MES rat has a balance defect due to impaired formation of otoconia in the utricles and saccules. Eosinophilia of the MES rat was normalized by introduction of a normal Cyba transgene. The mechanisms by which impairment of NADPH oxidase leads to eosinophilia in the MES rat are elusive. However, our study highlights the essential role of NADPH oxidase in homeostatic regulation of innate immunity beyond conventional microbicidial functions.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
CYBA	Human	Eosinophilia		ISO	Cyba (Rattus norvegicus)	DNA:deletion:splice junction:	RGD
Cyba	Rat	Eosinophilia		IAGP		DNA:deletion:splice junction:	RGD
Cyba	Mouse	Eosinophilia		ISO	Cyba (Rattus norvegicus)	DNA:deletion:splice junction:	RGD
Cyba^m1Sdi	Rat	Eosinophilia		IAGP			RGD
MES/Slc	Rat	Eosinophilia		IAGP			RGD

Phenotype Annotations Click to see Annotation Detail View

Mammalian Phenotype

Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Cyba	Rat	absent otoliths		IAGP		DNA:deletion:splice junction:	RGD
Cyba^m1Sdi	Rat	absent otoliths		IAGP		DNA:deletion:splice junction:	RGD
MES/Slc	Rat	absent otoliths		IAGP		DNA:deletion:splice junction:	RGD
Cyba	Rat	decreased NAD(P)H oxidase activity		IAGP		DNA:deletion:splice junction:	RGD
Cyba^m1Sdi	Rat	decreased NAD(P)H oxidase activity		IAGP		DNA:deletion:splice junction:	RGD
MES/Slc	Rat	decreased NAD(P)H oxidase activity		IAGP			RGD

Objects Annotated

Genes (Rattus norvegicus)

Cyba (cytochrome b-245 alpha chain)

Cyba^m1Sdi (cytochrome b-245 alpha chain;mutant 1,Sdi)

Genes (Mus musculus)

Cyba (cytochrome b-245, alpha polypeptide)

Genes (Homo sapiens)

CYBA (cytochrome b-245 alpha chain)

Strains

MES/Slc (Matsumoto Eosinophilia Shinshu)

Additional Information

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Pivotal Advance: Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba).

Mammalian Phenotype