Street V A, McKee-Johnson J W, Fonseca R C, Tempel B L, Noben-Trauth K
The Virginia Merrill Bloedel Hearing Research Center and Department of Otolaryngology-Head and Neck Surgery, University of Washington School of Medicine, Seattle 98195-7923, USA.
Nat Genet. 1998 Aug;19(4):390-4. doi: 10.1038/1284.
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.
听力损失是人类最常见的感觉缺陷。由于小鼠和人类的听觉系统具有保守性，对小鼠模型的研究已经预测了几种人类耳聋基因，并鉴定出了与听力有关的新基因。耳聋蹒跚（dfw）小鼠突变体耳聋，并表现出前庭/运动失衡。在此我们报告，编码质膜钙ATP酶2型泵（Atp2b2，也称为Pmca2）的基因在dfw中发生了突变。dfw DNA中的A→G核苷酸转换在一个高度保守的氨基酸位置导致甘氨酸到丝氨酸的替换，而在第二个等位基因dfw2J中，一个2碱基对的缺失导致移码，预测会产生截短的蛋白质。在野生型小鼠的耳蜗中，Atp2b2蛋白定位于静纤毛和毛细胞的基底外侧壁，但在dfw2J小鼠中未检测到。这表明Atp2b2的突变可能通过影响静纤毛中的感觉转导以及基底外侧膜的神经递质释放而导致耳聋和失衡。dfw和dfw2J中影响Atp2b2的这些突变是在哺乳动物质膜钙泵中首次发现的，并且定义了一类直接影响毛细胞生理学的新的耳聋基因。
