Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.
Otitis media (OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM.
Parkinson
Nicholas
N
Mammalian Gentics Unit, Medical Research Council, Harwell, United Kingdom.
Hardisty-Hughes
Rachel E
RE
Tateossian
Hilda
H
Tsai
Hsun-Tien
HT
Brooker
Debra
D
Morse
Sue
S
Lalane
Zuzanna
Z
MacKenzie
Francesca
F
Fray
Martin
M
Glenister
Pete
P
Woodward
Anne-Marie
AM
Polley
Sian
S
Barbaric
Ivana
I
Dear
Neil
N
Hough
Tertius A
TA
Hunter
A Jackie
AJ
Cheeseman
Michael T
MT
Brown
Steve D M
SD
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004432:Ear, Middle / Q000166:cytology / Q000473:pathology; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006098:Granulocytes / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009666:Nose / Q000166:cytology / Q000473:pathology; D010033:Otitis Media / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D011519:Proto-Oncogenes / Q000235:genetics*; D013047:Specific Pathogen-Free Organisms; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D014157:Transcription Factors