GENETICS OF A NEW MOUSE MODEL FOR DEAFNESS

Jackson Laboratory, Bar Harbor ME

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Abstract

DESCRIPTION (adapted from applicant's abstract): Genetic impairment of hearing affects about one in every 2,000 children. Identification of genes leading to hearing impairment is essential for understanding factors necessary for normal auditory function and for development of therapeutic strategies. The genetic analysis of mouse deafness mutations has proven instrumental in the identification of several human deafness genes. A new mutation causing hearing and balance defects spontaneously arose in a colony of BALB/cByJ inbred mice at The Jackson Laboratory. The recessive mutation was named 'hypoplasia of the membranous labyrinth' (symbol hml) because it mainly affects inner ear morphology and development. The human homolog of the gene responsible for the hml phenotype in mice may play a role in the etiology and pathogenesis of some cases of human inherited deafness. Currently the pathogenetic mechanism and the identity of hml are not known. A small panel of intercross mice was used to map the hml locus to the middle region of mouse chromosome (Chr) 10. The genetic map position of the mouse hml gene suggests that the homologous human gene may be located on Chr 9pl3, where a particular form of genetic deafness in humans (DFNB15) has been previously mapped. In order to characterize the genetic and developmental dysfunction responsible for this morphogenetic inner ear mutation in mice, and ultimately extend that new found knowledge to improve our understanding of DFNB15 or other deafness traits in humans, the identification and characterization of the hml gene needs to be carried out. Aim 1. Generate a high-resolution genetic map of the region surrounding hml and screen candidate genes for the mutation. Aim 2. Construct a physical contig of YACS and BACS clones across the minimal genetic region. Aim 3. Fully characterize the development and pathology of inner ears from hml/hml mice compared with hml/+ and +/+ controls.