Mcph1-Deficient Mice Reveal a Role for MCPH1 in Otitis Media

Jing Chen,Vinit B Mahajan,Karen P Steel,Gordon Dougan,Ozama Ismail,David J Adams,Valerie E Vancollie,Stephen H Tsang,Simon Clare,Neil Ingham,Rebecca E Mcintyre,Claire Raisen,Jacqueline K White,Patrick Callaerts

doi:10.1371/journal.pone.0058156

Jing Chen, Vinit B Mahajan + Show 12 more

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https://doi.org/10.1371/journal.pone.0058156

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Abstract

Otitis media is a common reason for hearing loss, especially in children. Otitis media is a multifactorial disease and environmental factors, anatomic dysmorphology and genetic predisposition can all contribute to its pathogenesis. However, the reasons for the variable susceptibility to otitis media are elusive. MCPH1 mutations cause primary microcephaly in humans. So far, no hearing impairment has been reported either in the MCPH1 patients or mouse models with Mcph1 deficiency. In this study, Mcph1-deficient (Mcph1tm1a /tm1a) mice were produced using embryonic stem cells with a targeted mutation by the Sanger Institute's Mouse Genetics Project. Auditory brainstem response measurements revealed that Mcph1tm1a /tm1a mice had mild to moderate hearing impairment with around 70% penetrance. We found otitis media with effusion in the hearing-impaired Mcph1tm1a /tm1a mice by anatomic and histological examinations. Expression of Mcph1 in the epithelial cells of middle ear cavities supported its involvement in the development of otitis media. Other defects of Mcph1tm1a /tm1a mice included small skull sizes, increased micronuclei in red blood cells, increased B cells and ocular abnormalities. These findings not only recapitulated the defects found in other Mcph1-deficient mice or MCPH1 patients, but also revealed an unexpected phenotype, otitis media with hearing impairment, which suggests Mcph1 is a new gene underlying genetic predisposition to otitis media.

Highlights

Otitis media (OM), inflammation of the middle ear, is the most common cause of hearing impairment in children
Quantitative real-time PCR revealed the residual transcript of microcephalin 1 (Mcph1) in the homozygous mice is only 1– 4% of the level compared to the wild type mice and the residual levels vary in different organs (Figure 1C)
Auditory Brainstem Response (ABR) thresholds were raised uniformly across all frequencies tested and the growth of amplitude of the waveform with increasing sound stimulation above threshold was similar in mutants and controls, both features consistent with a conductive hearing impairment

Summary

Introduction

Otitis media (OM), inflammation of the middle ear, is the most common cause of hearing impairment in children. Many factors are thought to contribute to the development and persistence of OM including: environmental factors such as smoking and type of child care; anatomical dysmorphology; Eustachian-tube function; adaptive and innate immune system function; viral and bacterial load; and genetic predisposition. Clinical studies of OM are limited by the wide range of environmental elements involved. Can be bred in a controlled environment, minimising the variation arising from the environment, making it a useful model for building an understanding of the genetic pathways and mechanisms underlying OM. As summarised in a recent review [4], mouse models involving disruption of genes functioning as transcription factors, and genes involved in apoptosis, the immune system, ciliary function and in mucopolysaccharidoses revealed that many pathways and processes can contribute to the development of OM

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