Mutation of the novel gene Tmie results in sensory cell defects in the inner ear of spinner, a mouse model of human hearing loss DFNB6.
The recessive mutation at the mouse spinner (sr) locus results in hearing loss and vestibular dysfunction due to neuroepithelial defects in the inner ear. Using a positional cloning strategy, we have identified the mutant locus responsible for this pathology. The affected gene (Tmie) lies within a 40 kb deletion in the original sr allele. In a newly identified allele, Tmie contains a nonsense mutation expected to truncate the C-terminal end of its product. The 153 amino acid protein encoded by the gene shows no similarity to other known proteins, and is predicted to contain a signal peptide and at least one transmembrane domain. Tmie transcripts were identified in several tissues, including the cochlea. Loss of function of Tmie results in postnatal alterations of sensory hair cells in the cochlea, including defects in stereocilia, the apical projections of hair cells that are important in mechanotransduction of sound. These morphological defects are associated with a profound failure to develop normal auditory function. Consistent with a conserved role for this gene in the cochlea, the genetic mapping data presented here support human TMIE as the gene affected at DFNB6, a non-syndromic hearing loss locus. The spinner mutant is thus a valuable model for insight into mechanisms of human deafness and development of sensory cell function.
Mitchem
Kristina L
KL
Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Hibbard
Ellen
E
Beyer
Lisa A
LA
Bosom
Ken
K
Dootz
Gary A
GA
Dolan
David F
DF
Johnson
Kenneth R
KR
Raphael
Yehoash
Y
Kohrman
David C
DC
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006198:Hair Cells, Auditory / Q000002:abnormalities / Q000648:ultrastructure; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D009154:Mutation; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
D018076:DNA, Complementary; D008565:Membrane Proteins; C466299:TMIE protein, human