Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice

Abstract

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 hearing. 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 A-->G nucleotide transition in dfw DNA causes a glycine-to-serine substitution at a highly conserved amino-acid position, whereas in a second allele, dfw2J, 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 stereocilia as well as neurotransmitter release from the basolateral membrane. 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.

Ageing and hearing loss

“…A major QTL for AHL (Ahl1 ) was identified on mouse chromosome 10, overlapping with the modifier of the deaf waddler locus (mdfw ) region. Several loci associated with hearing function map near the mdfw locus, including the mouse mutations waltzer and Jackson circler [39]. In humans, the Usher syndrome type 1D gene and the recessive non-syndromic deafness gene DFNB12 have been mapped to chromosome 10q21-q22, which is orthologous to the mdfw region in the mouse.…”

“…The gene responsible for the dfw mutation has been identified as a plasma membrane ATPase type 2-Ca 2+ transporter pump (Atp2b2 ). In the cochlea, the Atp2b2 protein was localized to stereocilia and the basolateral wall of hair cells, implying that it may be essential for the removal of the Ca 2+ from subcellular domains of both auditory and vestibular hair cells [39]. Genetic fine mapping suggests that the mouse waltzer mutation within cadherin 23 (Cdh23 v ) is allelic with mdfw [40].…”

Progressive Hearing Loss and Increased Susceptibility to Noise-Induced Hearing Loss in Mice Carrying a Cdh23 but not a Myo7a Mutation

“…Perhaps the most relevant gene in the context of Cdh23 function is Atp2b2. This gene is mutated in deafwaddler mice causing deafness in homozygotes (Street et al 1998). Kozel et al (2002) recently demonstrated that deafwaddler heterozygotes are more susceptible to noise-induced hearing loss than their wild-type littermates.…”

“…A modifier of this gene (mdfw), causes hearing loss in deafwaddler heterozygotes, has been mapped to the same chromosomal location as ahl and Cdh23, suggesting that all three may be allelic (Noben-Trauth et al 1997;Bryda et al 2001;Zheng and Johnson 2001). Atp2b2 encodes a plasma membrane Ca 2+ -ATPase pump that removes Ca 2+ from the stereocilia (Street et al 1998;Yamoah et al 1998). It is conceivable that disruption of Ca 2+ homeostasis in the stereocilia could affect Cdh23 function since the homophilic interaction between cadherins is Ca 2+ dependent (Leckband and Sivasankar 2000).…”

Changes in Cytochemistry of Sensory and Nonsensory Cells in Gentamicin-Treated Cochleas

“…In this study, decreased immunostaining for PMCA of the stereocilia and the cuticular plate of OHCs in gentamicin-treated ears was striking. The restricted presence of PMCA in the stereocilia and cuticular plate of OHCs (Crouch and Schulte 1995;Apicella et al 1997;Furuta et al 1998;Takahashi and Kitamura 1999;Street et al 1998) suggests that it may affect mechanoelectrical transduction through calcium ion regulation (see, e.g., Fettiplace et al 2001). It seems reasonable to assume that surviving hair cells with greatly reduced PMCA levels were not functioning normally.…”