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Salehi, Pezhman; Myint, Anthony; Kim, Young J.; Ge, Marshall X.; Lavinsky, Joel; Ho, Maria K.; Crow, Amanda L.; Cruz, Charlene; Monges-Hernadez, Maya; Wang, Juemei; Hartiala, Jaana; Zhang, Li I.; Allayee, Hooman; Lusis, Aldons J.; Ohyama, Takahiro; Friedman, Rick A.
Journal of the Association for Research in Otolaryngology, 10/2016, Letnik: 17, Številka: 5Journal Article
This study aimed to investigate the genetic causes of vestibular dysfunction. We used vestibular sensory-evoked potentials (VsEPs) to characterize the vestibular function of 35 inbred mouse strains selected from the Hybrid Mouse Diversity Panel and demonstrated strain-dependent phenotypic variation in vestibular function. Using these phenotypic data, we performed the first genome-wide association study controlling for population structure that has revealed two highly suggestive loci, one of which lies within a haplotype block containing five genes ( Stard6 , 4930503L19Rik , Poli , Mbd2 , Dcc ) on Chr. 18 (peak SNP rs29632020), one gene, deleted in colorectal carcinoma ( Dcc ) has a well-established role in nervous system development. An in-depth analysis of Dcc -deficient mice demonstrated elevation in mean VsEP threshold for Dcc +/− mice (−11.86 dB) compared to wild-type (−9.68 dB) littermates. Synaptic ribbon studies revealed Dcc −/− (P0) and Dcc +/− (6-week-old) mice showed lower density of the presynaptic marker (CtBP2) as compared to wild-type controls. Vestibular ganglion cell counts of Dcc −/− (P0) was lower than controls. Whole-mount preparations showed abnormal innervation of the utricle, saccule, and crista ampullaris at E14.5, E16.5, and E18.5. Postnatal studies were limited by the perinatal lethality in Dcc −/− mice. Expression analyses using in situ hybridization and immunohistochemistry showed Dcc expression in the mouse vestibular ganglion (E15.5), and utricle and crista ampullaris (6-week-old), respectively. In summary, we report the first GWAS for vestibular functional variation in inbred mice and provide evidence for the role of Dcc in the normal innervation of the peripheral vestibular system.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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