Abstract
Over 120 loci are known to cause inherited hearing loss in humans. The deafness gene has been identified for only half of these loci. With the aim of identifying some of the remaining deafness genes, we performed an ethylnitrosourea mutagenesis screen for deaf mice. We isolated two mutants with semi-dominant hearing loss, Deaf11 and Deaf13. Both contained causative mutations in Atp2b2, which encodes the plasma membrane calcium ATPase 2. The Atp2b2 Deaf11 mutation leads to a p. I1023S substitution in the tenth transmembrane domain. The Atp2b2 Deaf13 mutation leads to a p. R561S substitution in the catalytic core. Mice homozygous for these mutations display profound hearing loss. Heterozygotes display mild to moderate, progressive hearing loss.
Highlights
Inherited hearing loss affects 1 in 500 children [1]
The Atp2b2Deaf11/Deaf11 and Atp2b2Deaf13/Deaf13 hair cells had abnormal morphology indicative of degeneration (Figure 4). These results suggest that the loss of plasma membrane calcium ATPase 2 (PMCA2) activity may lead to degeneration of hair cells in Atp2b2Deaf11/Deaf11 and Atp2b2Deaf13/Deaf13 mice
This study demonstrates that isoleucine 1023 and arginine 561 are functionally important in PMCA2
Summary
Inherited hearing loss affects 1 in 500 children [1]. Over 120 loci have been linked to non-syndromic hearing loss in humans but only 57 genes have been identified (http:// hereditaryhearingloss.org) [2], leaving many patients without a genetic diagnosis. Endolymph contains a high concentration of potassium ions and contains calcium ions [3]. Sound waves bend the stereocilia, stretching the tip links between them and pulling open a mechanoelectrical transduction (MET) channel [3]. This allows potassium and calcium ions from the endolymph to enter the hair cell, causing the hair cell to signal to synapsing neurons of the auditory nerve [3]
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