Hearing loss in a mouse model of Muenke syndrome

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA.
Human Molecular Genetics (Impact Factor: 6.39). 10/2008; 18(1):43-50. DOI: 10.1093/hmg/ddn311
Source: PubMed


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 (Fgfr3(P244R)). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3(P244R) mice showed dominant, fully penetrant hearing loss that was more severe than that in 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.

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    • "In addition to supporting-cell defects, the outer hair cells and their innervation by spiral ganglia fibres are also disrupted (Puligilla et al., 2007). Thus, FGF signalling via FGFR3 regulates the fate decision between two populations of supporting cells (Colvin et al., 1996; Hayashi et al., 2007; Mansour et al., 2009, 2013; Puligilla et al., 2007), influencing hair cell function indirectly. Therefore, FGFR3, like WHSC1, might contribute to sensorineural hearing loss in individuals with WHS (Battaglia and Carey, 1999). "
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    ABSTRACT: WHSC1 is a histone methyltransferase (HMT) that catalyses the addition of methyl groups to lysine 36 on histone 3. In humans, WHSC1 haploinsufficiency is associated with all known cases of Wolf-Hirschhorn syndrome (WHS). The cardinal feature of WHS is a craniofacial dysmorphism, which is accompanied by sensorineural hearing loss in 15% of patients. Here, we show that WHSC1-deficient mice display craniofacial defects that overlap with WHS including cochlea anomalies. While auditory hair cells are specified normally, their stereocilia hair bundles required for sound perception, fail to develop the appropriate morphology. Furthermore, the orientation and cellular organisation of cochlear hair cells and their innervation are defective. These findings identify, for the first time, the likely cause of sensorineural hearing loss in WHS patients. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jun 2015 · Disease Models and Mechanisms
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    • "Interestingly, mutations in some components of the Fibroblast growth factor (Fgf) signaling pathway cause inner ear structural defects that appear similar to those of the hypothyroid phenotype. In particular, mutations in Fgf receptor 3 (Fgfr3) lead to disruptions in tissue structure, including a collapsed tunnel of Corti, and cause auditory defects in both mice and humans [13,22-24]. These disruptions have been attributed to both a lack of differentiation of PCs and malformation in PC microtubule development [23]. "
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    ABSTRACT: Background Thyroid hormones regulate growth and development. However, the molecular mechanisms by which thyroid hormone regulates cell structural development are not fully understood. The mammalian cochlea is an intriguing system to examine these mechanisms, as cellular structure plays a key role in tissue development, and thyroid hormone is required for the maturation of the cochlea in the first postnatal week. Results In hypothyroid conditions, we found disruptions in sensory outer hair cell morphology and fewer microtubules in non-sensory supporting pillar cells. To test the functional consequences of these cytoskeletal defects on cell mechanics, we combined atomic force microscopy with live cell imaging. Hypothyroidism stiffened outer hair cells and supporting pillar cells, but pillar cells ultimately showed reduced cell stiffness, in part from a lack of microtubules. Analyses of changes in transcription and protein phosphorylation suggest that hypothyroidism prolonged expression of fibroblast growth factor receptors, and decreased phosphorylated Cofilin. Conclusions These findings demonstrate that thyroid hormones may be involved in coordinating the processes that regulate cytoskeletal dynamics and suggest that manipulating thyroid hormone sensitivity might provide insight into the relationship between cytoskeletal formation and developing cell mechanical properties.
    Full-text · Article · Feb 2013 · BMC Developmental Biology
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    • "However, in most of these models the patterning defect is part of a complex cochlear and organismal phenotype that additionally may include a truncated cochlea coil, ectopic hair cells in Kölliker's organ, planar cell polarity defects, innervation defects, increased number of inner hair cells, or neural tube defects. The patterning defect in ALR/LtJ is most similar to the organ of Corti phenotype in Spry2 -/-and Fgfr3 P244R mice, both of which show extra rows of outer hair cells and outer pillar cells (Mansour et al., 2009; Shim et al., 2005). This suggests that the underlying genetic variant(s) in ALR/LtJ may target the Fgfr3 or Spry2 signaling pathways. "
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    ABSTRACT: Progressive sensorineural hearing loss in humans is a common and debilitating impairment. Sensorineural deafness in inbred strains of mice is a similarly common and genetically diverse phenotype providing experimental models to study the underlying genetics and the biological effects of the risk factors. Here, we report that ALR/LtJ mice develop early-onset profound sensorineural hearing loss as evidenced by high-to-low frequency hearing threshold shifts, absent distortion-product otoacoustic emissions, and normal endocochlear potentials. Linkage analyses of a segregating backcross revealed three novel quantitative trait loci named sensorineural hearing loss (Snhl) -2, -3, and -4. The QTLs achieved very high LOD scores with markers on chromosome 1 (Snhl2, LOD: 12), chromosome 6 (Snhl3, LOD: 24) and chromosome 10 (Snhl4, LOD: 11). Together, they explained 90% of the phenotypic variance. While Snhl2 and Snhl3 affected hearing thresholds across a broad range of test frequencies, Snhl4 caused primarily high-frequency hearing loss. The hearing impairment is accompanied by an organ of Corti patterning defect that is characterized by the ectopic expression of supernumerary outer hair cells organized in rows along the abneural site of the sensory epithelium in the presence of unaltered planar polarity and otherwise normal cochlear duct morphology. Cloning the Snhl2, -3, and -4 genes in the ALR/LtJ mice may provide important genetic and mechanistic insights into the pathology of human progressive sensorineural deafness.
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