The Deaf Mouse Mutant Jeff (Jf) is a Single Gene Model of Otitis Media

Hardisty, Rachel E.; Erven, Alexandra; Logan, Karen M.; Morse, Susan; Guionaud, Sylvia; Sancho–Oliver, Sara; Hunter, A. Jackie; Brown, Steve; Steel, Karen P.

doi:10.1007/s10162-002-3015-9

Cited by 74 publications

(83 citation statements)

References 30 publications

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“…Significant P-values are shown in bold, those approaching significance are shown in italics. On a C3H/HeH background, 9 Jf homozygous mutant mice have severe developmental defects, including cleft palate, which is a developmental condition known to increase the prevalence of OM in humans, 15 whereas heterozygous Jf/ þ mice demonstrate mild craniofacial abnormalities, such as a shortened snout and smaller eustachian tubes. Whilst these craniofacial abnormalities may contribute to the OM susceptibility observed in these mice, it has been shown that on a C57BL/6 background Jf/ þ mice have no apparent craniofacial defects although they do still develop OM (SD Brown, unpublished data 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…Functional data from mouse models, 8,9 combined with Ingenuity pathway analysis (Ingenuity Systems, http://www.ingenuity.com), indicated that both gene products interact with the TGFb pathway and thus other key genes in this pathway-SMAD2, SMAD3, SMAD4 and SMAD7-were also investigated. For genotyping in the family cohort, a minimum of two haplotype tagging (tag) SNPs were selected for each gene using data from the Caucasian population in the International HapMap Project.…”

Section: Dna Extractionmentioning

confidence: 99%

“…Heterozygous Jf/ þ mice develop COME 28 days after birth, again in the absence of severe craniofacial abnormalities. 9 The Jf mutation maps to the Fbxo11 gene. Interestingly, both mutant mouse strains develop chronic OM in specific pathogen-free conditions.…”

Section: Introductionmentioning

confidence: 99%

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FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children

et al. 2011

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Otitis media (OM) is a common childhood disease characterised by middle ear inflammation following infection. Susceptibility to recurrent acute OM (rAOM) and chronic OM with effusion (COME) is highly heritable. Two murine mutants, Junbo and Jeff, spontaneously develop severe OM with similar phenotypes to human disease. Fine-mapping of these mutants identified two genes (Evi1 and Fbxo11) that interact with the transforming growth factor b (TGFb) signalling pathway. We investigated these genes, as well as four Sma-and Mad-related (SMAD) genes of the TGFb pathway, as candidate rAOM/COME susceptibility genes in two predominantly Caucasian populations. Single-nucleotide polymorphisms (SNPs) within FBXO11 (family-based association testing Z-Score ¼ 2.61; P best ¼ 0.009) were associated with severe OM in family-based analysis of 434 families (561 affected individuals) from the Western Australian Family Study of OM. The FBXO11 association was replicated by directed analysis of Illumina 660W-Quad Beadchip data available for 253 cases and 866 controls (OR ¼ 1.55 (95% CI 1.28-1.89); P best ¼ 6.9 Â 10 À6 ) available within the Western Australian Pregnancy Cohort (Raine) Study. Combined primary and replication results show P combined ¼ 2.98 Â 10 À6 . Neither cohort showed an association with EVI1 variants. Family-based associations at SMAD2 (P ¼ 0.038) and SMAD4 (P ¼ 0.048) were not replicated. Together, these data provide strong evidence for FBXO11 as a susceptibility gene for severe OM.

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Section: Discussionmentioning

confidence: 99%

Section: Dna Extractionmentioning

confidence: 99%

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FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children

et al. 2011

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“…Middle ear inflammation and increased otitis media susceptibility have been observed in mice with mutations in Eya1, Six1, and Fbxo11 (27,(30)(31)(32). To determine whether Eya4 -/-mice developed otitis media because these genes were dysregulated by the absence of Eya4, we compared expression in wild- The moET, isthmus, cartilaginous segment (cartET), and opening of the eustachian tube within the nasopharynx (OpNP) are indicated on the wild-type 3D reconstruction.…”

Section: Production Of Eya4-deficient Mice the Endogenous Eya4 Gene Wasmentioning

confidence: 99%

Eya4-deficient mice are a model for heritable otitis media

Depreux¹,

Darrow²,

Conner³

et al. 2008

J. Clin. Invest.

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Otitis media is an extremely common pediatric inflammation of the middle ear that often causes pain and diminishes hearing. Vulnerability to otitis media is due to eustachian tube dysfunction as well as other poorly understood factors, including genetic susceptibility. As EYA4 mutations cause sensorineural hearing loss in humans, we produced and characterized Eya4-deficient (Eya4 -/-) mice, which had severe hearing deficits. In addition, all Eya4 -/-mice developed otitis media with effusion. Anatomic studies revealed abnormal middle ear cavity and eustachian tube dysmorphology; thus, Eya4 regulation is critical for the development and function of these structures. We suggest that some human otitis media susceptibility reflects underlying genetic predisposition in genes like EYA4 that regulate middle ear and eustachian tube anatomy.

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“…In addition to genetically engineered mouse models, chemical mutagenesis using N-ethyl-N-nitrosourea (ENU), which causes primarily single-nucleotide mutations, has produced numerous new mouse models for studying human disease. Many of these mutants carry a novel functional mutation in a known gene (7)(8)(9)(10)(11). For known genes, having multiple models with a variety of unique mutations allows a survey of phenotypic differences and functional annotation of genes and their products.…”

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confidence: 99%

A new mouse mutant for the LDL receptor identified using ENU mutagenesis

Svenson

Ahituv

Durgin

et al. 2008

Journal of Lipid Research

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In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This lossof-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality. The incidence and progression of atherosclerosis remains a challenge for public health intervention and medical research strategies. Mouse models have been of great utility in meeting this challenge and have enabled systematic evaluation of genetic and environmental influences on the pathogenesis of this disease. Lipoproteins and their receptors play crucial roles in cholesterol homeostasis and, when functionally impaired, can accelerate atherogenesis. Mice with targeted mutations resulting in loss of function and those engineered for overexpression of apolipoproteins, their receptors, and key enzymes in lipid metabolism have been used extensively to investigate the complex etiology of atherosclerosis and to develop effective approaches to treatment (1-6). In addition to genetically engineered mouse models, chemical mutagenesis using N-ethyl-N-nitrosourea (ENU), which causes primarily single-nucleotide mutations, has produced numerous new mouse models for studying human disease. Many of these mutants carry a novel functional mutation in a known gene (7-11). For known genes, having multiple models with a variety of unique mutations allows a survey of phenotypic differences and functional annotation of genes and their products. Causative mutations in numerous ENU mutants identified from large-scale mutagenesis programs worldwide, collectively representing a broad spectrum of disease-related phenotypes, have yet to be identified, and still hold promise of revealing novel genes.Here we describe the identification and initial characterization of a new mouse model of high cholesterol and atherosclerosis generated using ENU mutagenesis and high-throughput phenotyping. Candidate gene sequencing identified a point mutation in the LDL receptor (Ldlr) gene. Comparison of this mutant with the well-characterized Ldlr knockout (KO) mouse model reveals certain phenotypic differences and supports it as a new tool for the study of familial hypercholesterolemia (FH) and atherosclerosis. METHODS Mice and husbandryNonmutagenized C57BL/6J (B...

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The Deaf Mouse Mutant Jeff (Jf) is a Single Gene Model of Otitis Media

Cited by 74 publications

References 30 publications

FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children

FBXO11, a regulator of the TGFβ pathway, is associated with severe otitis media in Western Australian children

Eya4-deficient mice are a model for heritable otitis media

A new mouse mutant for the LDL receptor identified using ENU mutagenesis

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