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Human Molecular Genetics Advance Access published online on September 25, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn311
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Hearing loss in a mouse model of Muenke syndrome

Suzanne L. Mansour1,*, Stephen R. F. Twigg2, Rowena M. Freeland3, Steven A. Wall4, Chaoying Li1 and Andrew O. M. Wilkie2

1 Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA 2 Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK 3 Audiology Department, John Radcliffe Hospital, Oxford OX3 9DU, UK 4 Audiology Department and Oxford Craniofacial Unit, John Radcliffe Hospital, Oxford OX3 9DU, UK

* Corresponding Author: Suzanne L. Mansour Department of Human Genetics University of Utah 15 North 2030 East, Rm. 2100 Salt Lake City, UT 84112-5330, USA Phone: 801-585-6893 Fax: 801-581-7796 e-mail: suzi.mansour{at}genetics.utah.edu

Received August 5, 2008; Revised September 19, 2008; Accepted September 23, 2008

The heterozygous Pro250Arg substitution mutation in fibroblast growth factor receptor 3 (FGFR3), which increases ligand-dependent signalling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signalling plays dosage sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3P244R). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3P244R mice showed dominant, fully penetrant hearing loss that was more severe than that of Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters'-to-pillar cells) along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. In addition, there was excess outer hair cell development in the apical region. We conclude that low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome, and that the genetically equivalent mouse provides an excellent model that could be useful in testing hearing loss therapies aimed at manipulating the levels of FGF signalling in the inner ear.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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