Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QX, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Cereb Cortex. 2017 Dec 1;27(12):5831-5845. doi: 10.1093/cercor/bhx269.
Developmental dyslexia is a neurodevelopmental disorder that affects reading ability caused by genetic and non-genetic factors. Amongst the susceptibility genes identified to date, KIAA0319 is a prime candidate. RNA-interference experiments in rats suggested its involvement in cortical migration but we could not confirm these findings in Kiaa0319-mutant mice. Given its homologous gene Kiaa0319L (AU040320) has also been proposed to play a role in neuronal migration, we interrogated whether absence of AU040320 alone or together with KIAA0319 affects migration in the developing brain. Analyses of AU040320 and double Kiaa0319;AU040320 knockouts (dKO) revealed no evidence for impaired cortical lamination, neuronal migration, neurogenesis or other anatomical abnormalities. However, dKO mice displayed an auditory deficit in a behavioral gap-in-noise detection task. In addition, recordings of click-evoked auditory brainstem responses revealed suprathreshold deficits in wave III amplitude in AU040320-KO mice, and more general deficits in dKOs. These findings suggest that absence of AU040320 disrupts firing and/or synchrony of activity in the auditory brainstem, while loss of both proteins might affect both peripheral and central auditory function. Overall, these results stand against the proposed role of KIAA0319 and AU040320 in neuronal migration and outline their relationship with deficits in the auditory system.
发展性阅读障碍是一种神经发育障碍，由遗传和非遗传因素引起阅读能力受损。在迄今为止确定的易感性基因中，KIAA0319 是一个主要候选基因。在大鼠中的 RNA 干扰实验表明它参与皮质迁移，但我们无法在 Kiaa0319 突变小鼠中证实这些发现。鉴于其同源基因 Kiaa0319L（AU040320）也被提出在神经元迁移中发挥作用，我们询问是否 AU040320 的缺失单独或与 KIAA0319 一起缺失会影响发育中的大脑中的迁移。对 AU040320 和双 Kiaa0319；AU040320 敲除（dKO）的分析显示，皮层分层、神经元迁移、神经发生或其他解剖异常没有受损的证据。然而，dKO 小鼠在行为性噪声检测任务中表现出听觉缺陷。此外，点击诱发的听觉脑干反应记录显示 AU040320-KO 小鼠的 III 波振幅存在阈上缺陷，而 dKO 小鼠则存在更普遍的缺陷。这些发现表明 AU040320 的缺失破坏了听觉脑干的活动发射和/或同步性，而两种蛋白的缺失可能会影响外周和中枢听觉功能。总的来说，这些结果与 KIAA0319 和 AU040320 在神经元迁移中的拟议作用相悖，并概述了它们与听觉系统缺陷的关系。
