Mutations in a plasma membrane Ca2+-ATPase gene cause
deafness in deafwaddler mice
Valerie A. Street1, Jennifer W. McKee-Johnson1, Rosalia C. Fonseca1, Bruce L. Tempel1
& Konrad Noben-Trauth2
1
The Virginia Merrill Bloedel Hearing Research Center and Department of Otolaryngology-Head and Neck Surgery, Box 357923, University of Washington School of Medicine, Seattle, Washington 98195-7923, USA.
2
National Institutes of Health, National Institute on Deafness and Other Communication Disorders, Section on Murine Genetics, 5 Research Court, Rockville, Maryland 20850, USA.
Hearing loss is the most common sensory deficit in humans. Because
the auditory systems of mice and humans are conserved, studies on mouse models
have predicted several human deafness genes and identified new genes involved
in hearing1,
2. The deafwaddler (dfw) mouse mutant is
deaf and displays vestibular/motor imbalance. Here we report that the gene
encoding a plasma membrane Ca2+-ATPase type 2 pump (Atp2b2
, also known as Pmca2) is mutated in dfw. An AG nucleotide
transition in dfw DNA causes a glycine-to-serine substitution at a
highly conserved amino-acid position, whereas in a second allele, dfw
2J, a 2-base-pair deletion causes a frameshift that predicts a truncated
protein. In the cochlea, the protein Atp2b2 is localized to stereocilia and
the basolateral wall of hair cells in wild-type mice, but is not detected
in dfw2J mice. This indicates that mutation of Atp2b2
may cause deafness and imbalance by affecting sensory transduction in
stereocilia3 as well as neurotransmitter release from the basolateral
membrane4. These mutations affecting Atp2b2 in dfw
and dfw2J are the first to be found in a mammalian
plasma membrane calcium pump and define a new class of deafness genes that
directly affect hair-cell physiology.
G nucleotide
transition in dfw DNA causes a glycine-to-serine substitution at a
highly conserved amino-acid position, whereas in a second allele, dfw
2J, a 2-base-pair deletion causes a frameshift that predicts a truncated
protein. In the cochlea, the protein Atp2b2 is localized to stereocilia and
the basolateral wall of hair cells in wild-type mice, but is not detected
in dfw
2J mice. This indicates that mutation of Atp2b2
may cause deafness and imbalance by affecting sensory transduction in
stereocilia
