Mutation of a novel non-coding RNA causes vestibular malformation in the Epistatic circler mouse
By: by Kristina Anne Roberts
Published: 2009
Language: eng
Number of pages: 95
Description: The inner ear is a complex sensory organ responsible for the senses of hearing and balance. Within the inner ear, three semicircular canals (SCC) provide information about rotational movement of the head. Malformation of these canals can lead to dizziness and imbalance, and in mice, these defects often result in circling behavior. The Epistatic circler, a mouse mutant that displays rapid bidirectional circling due to malformation of the lateral SCC, was originally described in a small proportion of animals with a mixed genetic background derived from two inbred strains: SWR/J and C57L/J. Circling is the result of an epistatic interaction between a recessive gene on chromosome 14 (derived from SWR/J) and a dominant gene on chromosome 4 (derived from C57/J). While these loci were mapped previously, neither of the underlying genes has been identified.

We developed a mouse chromosome substitution strain (CSS) with an SWR/J chromosome 14 on a C57BL/10J genetic background and found that it exhibited circling behavior. We believe that this CSS is a new model of the Epistatic circler and have used it to positionally clone the chromosome 14 circling gene. Within our 445 Kb candidate interval, we identified a spliced EST expressed in the cristae of developing SCCs as a promising candidate. Based on mammalian conservation and ORF analysis, we predict that this novel gene functions as a long, non-coding RNA. Sequence analysis revealed that, in SWR, the first intron is disrupted by a 5.5 Kb endogenous retrovirus, resulting in reduced or absent gene expression in SWR mice and CSS circlers. We believe that this expression difference, when combined with the C57-derived gene on chromosome 4, is responsible for the circling phenotype of the Epistatic circler.
Notes: "April 2009."

Thesis (Ph.D., Division of Medical Sciences (Genetics))--Harvard University, 2009.

Includes bibliographical references.