Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Research School of Chemistry, College of Science, The Australian National University, Canberra, ACT, Australia.
Nat Commun. 2024 Nov 18;15(1):9885. doi: 10.1038/s41467-024-53663-x.
ABCB6 has been implicated in dyschromatosis universalis hereditaria, a condition characterized by hyperpigmented and hypopigmented skin macules. Dyschromatosis universalis hereditaria can also present with hearing loss. Dyschromatosis universalis hereditaria-associated mutations in ABCB6 have been reported, but the role of this protein in the inner ear has not been studied. Here we determine a high-resolution (2.93 Å) cryo-EM structure of ABCB6 and functionally characterized several dyschromatosis universalis hereditaria mutants. We find that the L356P mutant abolishes ABCB6 function, and affirm the underlying loss of ATP binding mechanism using molecular dynamics simulations based on our cryo-EM structure. To test the role of ABCB6 in the inner ear, we characterize Abcb6 (the ABCB6 homolog) in zebrafish. We show that Abcb6 suppression by morpholinos reduces inner ear and lateral line hair cell numbers. Morphants also lack the utricular otolith, which is associated with vestibular function. Co-injecting morpholinos with human ABCB6 mRNA partially rescues the morphant phenotype, suggesting that Abcb6 plays a developmental role in inner ear structures. Further, we show that Abcb6 knockout mice exhibit an increased auditory brainstem response threshold, resulting in reduced hearing sensitivity. Taken together, these data suggest ABCB6 plays a role in inner ear development and function.
ABCB6 已被牵连到色素失调症遗传性疾病中，这是一种以皮肤色素增多和减少的斑片为特征的疾病。色素失调症遗传性疾病也可能伴有听力损失。已经报道了 ABCB6 中的色素失调症遗传性疾病相关突变，但该蛋白在内耳中的作用尚未得到研究。在这里，我们确定了 ABCB6 的高分辨率（2.93Å）冷冻电镜结构，并对几种色素失调症遗传性疾病突变体进行了功能表征。我们发现 L356P 突变体完全丧失了 ABCB6 的功能，并通过基于我们的冷冻电镜结构的分子动力学模拟证实了其 ATP 结合机制的丧失。为了测试 ABCB6 在内耳中的作用，我们在斑马鱼中表征了 Abcb6（ABCB6 的同源物）。我们表明，通过 morpholino 抑制 Abcb6 会减少内耳和侧线毛细胞的数量。morphants 也缺乏与前庭功能相关的耳石。与人 ABCB6 mRNA 共注射可以部分挽救 morphant 表型，这表明 Abcb6 在内耳结构的发育中起着作用。此外，我们还发现 Abcb6 敲除小鼠的听觉脑干反应阈值增加，导致听力敏感度降低。综上所述，这些数据表明 ABCB6 在内耳发育和功能中发挥作用。
