Date of Award

12-2013

Level of Access

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Kenneth R. Johnson

Second Committee Member

Keith W. Hutchison

Third Committee Member

Mary Ann Handel

Abstract

The identification of mouse mutations that result in deafness is often the initial characterization of a genes involvement in hearing and inner ear development, providing a mouse model to study the molecular nature of the hearing process. A newly described mouse mutation named hyperspin (hspn) induces profound hearing loss and vestibular dysfunction in mice. Inner ear paint-fill analysis from embryonic hspn mice and wildtype controls reveal severe malformations in ears of hspn mice. Loss of the endolymphatic duct as well as anterior and posterior semicircular canals are observed as well as the variable loss of the lateral semicircular canal. This observation is highly similar to inner ear defects described in DIx5 -/- mice. The hspn mutation is localized to chromosome 6, approximately 840 kb away from Dlx5, and is a 123.4 kb deletion within the Slc25a13 gene. This gene is not known to play a role in inner ear development or hearing loss, mice that lack Slc25al3 transcripts are not described as having hearing loss. The protein encoded by Slc25al3, is a calcium-activated mitochondrial transporter called Citrin, and its absence contributes to varying forms of neonatal and adult onset citrullinemia. Another disorder, Split hand/split foot malformation 1 with sensorineural hearing loss (SHFM1D), is a complex disorder with degrees of severity involving deafness and ectrodactyly. Within the hspn deletion region also resides a putative DIx5 non-coding enhancer element eDlx#23, which may underlie Dlx5 dysregulation and thus the hspn phenotype observed. In this study we present the close association between the hspn phenotype and those observed in Dlx5 -/- mice, including phenotypic characterization and gene expression, to demonstrate the plausibility that the loss of Citrin is not a factor in the hearing loss phenotype, but rather it is an alternate genetic element, likely eDlx#23, that is responsible for the detected deafness, and that loss of such element may underlie the sensorineural deafness in SHFM1D; thus, creating a new mouse model to study deafness and elucidate the regulation of otic specific Dlx5.

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