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Doctor of Philosophy (PhD)
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This dissertation presents three new mouse models that help to study the functions of Enpp1, Atp6v1b1, and Tbx1 for ear development and function. asj (aging with stiffened joints) carries a missense mutation in the mouse Enpp1 gene. Enpp1 encodes the enzyme ENPP1 that regulate soft-tissue calcification and bone mineralization, and is associated with generalized arterial calcification of infancy and hypophosphatemic rickets in human patients. asj mutant mice show severe middle ear infection and tissue calcification, which provide a new mouse model to study otitis media and tympanoscleorosis. Atp6v1b1 encode a protein that is a subunit of the V-ATPase pump, which is the key regulator of pH homeostasis. Atp6v1b1 mutation is associated with human distal renal tubular acidosis (dRTA) with hearing loss; however, Atp6v1b1 knockout mice have mild kidney phenotype and normal hearing. vtx (vortex) mice carry a missense mutation in the mouse Atp6v1b1 gene on a MRL.Mpj background, that shows severe hearing loss and vestibular dysfunction. Transfer the vtx mutation to a B6 background did not cause hearing loss, indicating genetic background effects underlie this variation. We performed linkage backcross to map the genetic loci that modify the degree of hearing loss on the two different background strains and found statistically significant linkage with a region on Chr13. Because MRL-vtx mice exhibit enlargements of the endolymphatic sac and duct in the inner ear but do not exhibit the overt metabolic acidosis characteristic of dRTA, they provide a new genetic model for nonsyndromic deafness with enlarged vestibular aqueducts. TBX1 haploinsufficieny is associated with human DiGeorge syndrome. Tbx1 knockout mice are embryonic lethal and ear morphogenesis stops around E10 in the mutant mice. Study showed expression of TBX1 in the stria vascularis and vestibular dark cells, but because Tbx1 KO mice don’t have fully developed inner ear, new model is required to study Tbx1 function at later development stage. Tbx1wdml (windmill) mice carry a missense mutation in the mouse Tbx1 gene and have fully developed inner ear. Hearing loss and vestibular dysfunction correlate well with TBX1 expression in the stria vascularis and dark cells. This new Tbx1 mouse model provides a valuable tool to study Tbx1 function in the development of stria vascularis and semicircular canal.
Tian, Cong, "Molecular and Pathological Analyses of Three New Mouse Mutations That Affect Ear Development and Function" (2017). Electronic Theses and Dissertations. 2714.