» Articles » PMID: 38759260

The A2ml1-Knockout Mouse As an Animal Model for Non-syndromic Otitis Media

Overview
Specialty Pediatrics
Date 2024 May 17
PMID 38759260
Authors
Affiliations
Soon will be listed here.
Abstract

Background: Inflammation and infection of the middle ear, known as otitis media (OM), is a leading cause of hearing loss and the most frequently diagnosed disease in children worldwide. Traditionally, mouse models for OM rely on inducing acute infection through inoculation of the middle ear, e.g. with the human otopathogen non-typeable Haemophilus influenzae (NTHi), and with very few genetic models with spontaneous or chronic OM. A2ML1 variants, including loss-of-function variants, were associated with susceptibility to OM in humans, but no animal model has been reported for A2ml1-related OM. Here, we report our middle ear findings in a mouse line with a CRISPR-induced knockout (KO) of A2ml1.

Methods: Mice were X-rayed prior to harvest to determine if there are craniofacial or skeletal abnormalities. Tissue from mouse middle ears, as well as other upper respiratory mucosal tissues, were harvested. The harvested middle ear bullae were examined under microscope and submitted for histologic preparation to study phenotypic indications of OM. RNA samples isolated from middle ear tissue were assayed for expression of genes correlated with A2ML1 expression in humans.

Results: Data from a total of 119 mice (35 wildtype, 40 heterozygous, 44 homozygous) are presented here, with each analyses being performed on subsets of these mice. There were no significant craniofacial differences by genotype (n = 22). Findings in mice with the A2ml1-KO indicated an increased incidence of OM (n=29; odds ratio = 11; CI: 1.1, 573.6; Fisher exact two-sided p = 0.02) with tympanic membrane perforations or thickening, as well as cases of middle ear effusion, inflammatory cells, or fluid from histologic sections. Dsp was upregulated in the middle ear tissues of homozygous mice (Wilcoxon test p = 0.001).

Conclusion: Thus far, our results in this A2ml1-KO mouse line indicate spontaneous occurrence of OM and dysregulation of Dsp in the middle ear as a potential disease mechanism for A2ml1-related OM.

References
1.
Depreux F, Darrow K, Conner D, Eavey R, Liberman M, Seidman C . Eya4-deficient mice are a model for heritable otitis media. J Clin Invest. 2008; 118(2):651-8. PMC: 2213371. DOI: 10.1172/JCI32899. View

2.
van Trier D, van Nierop J, Draaisma J, van der Burgt I, Kunst H, Croonen E . External ear anomalies and hearing impairment in Noonan Syndrome. Int J Pediatr Otorhinolaryngol. 2015; 79(6):874-878. DOI: 10.1016/j.ijporl.2015.03.021. View

3.
Brinkmann J, Lissewski C, Pinna V, Vial Y, Pantaleoni F, Lepri F . The clinical significance of A2ML1 variants in Noonan syndrome has to be reconsidered. Eur J Hum Genet. 2020; 29(3):524-527. PMC: 7940614. DOI: 10.1038/s41431-020-00743-3. View

4.
Yang B, Tian C, Zhang Z, Han F, Azem R, Yu H . Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media. PLoS One. 2011; 6(7):e22622. PMC: 3144925. DOI: 10.1371/journal.pone.0022622. View

5.
Mathai S, Pedersen B, Smith K, Russell P, Schwarz M, Brown K . Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2015; 193(10):1151-60. PMC: 4872666. DOI: 10.1164/rccm.201509-1863OC. View