MUTATIONS IN A PLASMA-MEMBRANE CA2-ATPASE GENE CAUSE DEAFNESS IN DEAFWADDLER MICE()

Hearing loss is the most common sensory deficit in humans. Because the auditory systems of mice and humans are conserved, studies on mouse m odels have predicted several human deafness genes and identified new g enes involved in hearing(1,2). The deafwaddler (dfw) mouse mutant is d eaf and displays vestibular/motor imbalance. Here we report that the g ene encoding a plasma membrane Ca2+-ATPase type 2 pump (Atp2b2, also k nown as Pmca2) is mutated in dfw. An A-->G nucleotide transition in df w DNA causes a glycine-to-serine substitution at a highly conserved am ino-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 basol ateral wall of hair cells in wild-type mice, but is not detected in df w(2J) mice. This indicates that mutation of Atp2b2 may cause deafness and imbalance by affecting sensory transduction in stereocilia(3) as w ell as neurotransmitter release from the basolateral membrane(4). Thes e mutations affecting Atp2b2 in dfw and dfw(2J) are the first to be fo und in a mammalian plasma membrane calcium pump and define a new class of deafness genes that directly affect hair-cell physiology.