Dataset Information

Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse.

ABSTRACT: Inflammation of the middle ear cavity (otitis media) and the abnormal deposition of bone at the otic capsule are common causes of conductive hearing impairment in children and adults. Although a host of environmental factors can contribute to these conditions, a genetic predisposition has an important role as well. Here, we analyze the Tail-short (Ts) mouse, which harbors a spontaneous semi-dominant mutation that causes skeletal defects and hearing loss. By genetic means, we show that the Ts phenotypes arise from an 18-kb deletion/insertion of the Rpl38 gene, encoding a ribosomal protein of the large subunit. We show that Ts mutants exhibit significantly elevated auditory-brain stem response thresholds and reduced distortion-product otoacoustic emissions, in the presence of normal endocochlear potentials and typical inner ear histology suggestive of a conductive hearing impairment. We locate the cause of the hearing impairment to the middle ear, demonstrating over-ossification at the round window ridge, ectopic deposition of cholesterol crystals in the middle ear cavity, enlarged Eustachian tube, and chronic otitis media with effusion all beginning at around 3 weeks after birth. Using specific antisera, we demonstrate that Rpl38 is an ?8-kDa protein that is predominantly expressed in mature erythrocytes. Finally, using an Rpl38 cDNA transgene, we rescue the Ts phenotypes. Together, these data present a previously uncharacterized combination of interrelated middle ear pathologies and suggest Rpl38 deficiency as a model to dissect the causative relationships between neo-ossification, cholesterol crystal deposition, and Eustachian tubes in the etiology of otitis media.

SUBMITTER: Noben-Trauth K

PROVIDER: S-EPMC3024801 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse.

Noben-Trauth Konrad K Latoche Joseph R JR

The Journal of biological chemistry 20101109 4

Inflammation of the middle ear cavity (otitis media) and the abnormal deposition of bone at the otic capsule are common causes of conductive hearing impairment in children and adults. Although a host of environmental factors can contribute to these conditions, a genetic predisposition has an important role as well. Here, we analyze the Tail-short (Ts) mouse, which harbors a spontaneous semi-dominant mutation that causes skeletal defects and hearing loss. By genetic means, we show that the Ts phe ...[more]

PMID: 21062742

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Project description:BackgroundProteins found in middle ear effusion play crucial roles in the physiological and pathological processes of otitis media with effusion (OME), influencing the etiology and clinical characteristics of this disease. The qualitative and quantitative composition of these proteins depending on the underlying pathogenesis of middle ear effusion. Understanding their physiological and pathological functions is of great importance.MethodsWe collected samples from 19 volunteers diagnosed with OME. After offline separation using high-pH reversed-phase liquid chromatography (RPLC), the pooled sample was subjected to LC-MS/MS analysis to obtain a comprehensive profile of the OME proteome. Functional analysis was performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity Pathway Analysis (IPA) annotations. Data-independent acquisition (DIA) technology was utilized to analyze samples and fix whether the OME proteome could replicate the pathophysiological features associated with this disease. We conducted a differential proteomic analysis between patients with simple OME and patients who had received radiotherapy. The radiotherapy-reduced group was further divided into two subgroups: nasopharyngeal carcinoma (NPC) and other types of carcinoma. Parallel reaction monitoring (PRM) technology was used for validation of 36 differentially expressed proteins (DEPs).ResultsA number of 732 proteins were identified in the OME proteome database. Among them, 527 proteins were quantified using peak intensity-based semi-quantification (iBAQ), covering a wide dynamic range of approximately 8 orders of magnitude. Based on the functional analysis, we proposed a hypothetical mechanism of OME.ConclusionThis study managed to put up an inclusive analysis of the OME proteome, establishing the first human OME proteome database. We focused on differential proteomic analysis among different groups to gain a more comprehensive concept of the OME proteome and search for meaningful biomarkers.

Project description:Objective: Otitis media is known to alter expression of cytokine and other genes in the mouse middle ear and inner ear. However, whole mouse genome studies of gene expression in otitis media have not previously been undertaken. Ninety-nine percent of mouse genes are shared in the human, so these studies are relevant to the human condition. Methods: To assess inflammation-driven processes in the mouse ear, gene chip analyses were conducted on mice treated with trans-tympanic heat-killed Hemophilus influenza using untreated mice as controls. Middle and inner ear tissues were separately harvested at 6 hours, RNA extracted, and samples for each treatment processed on the Affymetrix 430 2.0 Gene Chip for expression of its 34,000 genes. Results: Statistical analysis of gene expression compared to control mice showed significant alteration of gene expression in 2,355 genes, 11% of the genes tested and 8% of the mouse genome. Significant middle and inner ear upregulation (fold change >1.5, p<0.05) was seen in 1,081 and 599 genes respectively. Significant middle and inner ear downregulation (fold change <0.67, p<0.05) was seen in 978 and 287 genes respectively. While otitis media is widely believed to be an exclusively middle ear process with little impact on the inner ear, the inner ear changes noted in this study were numerous and discrete from the middle ear responses. This suggests that the inner ear does indeed respond to otitis media and that its response is a distinctive process. Numerous new genes, previously not studied, are found to be affected by inflammation in the ear. Conclusion: Whole genome analysis via gene chip allows simultaneous examination of expression of hundreds of gene families influenced by inflammation in the middle ear. Discovery of new gene families affected by inflammation may lead to new approaches to the study and treatment of otitis media. There are 8 control samples and 9 samples trans-tympanically injected with H flu 10e9 for 6 hours. Each sample is from a single animal.

Dataset Information

Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse.

Publications

Ectopic mineralization in the middle ear and chronic otitis media with effusion caused by RPL38 deficiency in the Tail-short (Ts) mouse.

Similar Datasets

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