Barnes Terra D, Wozniak David F, Gutierrez Joanne, Han Tae-Un, Drayna Dennis, Holy Timothy E
Department of Neuroscience, Washington University School of Medicine in St. Louis, Campus Box 8108, 660 S. Euclid Avenue, St. Louis, MO 63110-1093, USA.
Department of Psychiatry, Campus Box 8134, and the Taylor Family Institute for Innovative Psychiatric Research, Campus Box 8108, Washington University School of Medicine in St. Louis, 660 S. Euclid Avenue, St. Louis, MO 63110-1093, USA.
Curr Biol. 2016 Apr 13. doi: 10.1016/j.cub.2016.02.068.
A promising approach to understanding the mechanistic basis of speech is to study disorders that affect speech without compromising other cognitive or motor functions. Stuttering, also known as stammering, has been linked to mutations in the lysosomal enzyme-targeting pathway, but how this remarkably specific speech deficit arises from mutations in a family of general "cellular housekeeping" genes is unknown. To address this question, we asked whether a missense mutation associated with human stuttering causes vocal or other abnormalities in mice. We compared vocalizations from mice engineered to carry a mutation in the Gnptab (N-acetylglucosamine-1-phosphotransferase subunits alpha/beta) gene with wild-type littermates. We found significant differences in the vocalizations of pups with the human Gnptab stuttering mutation compared to littermate controls. Specifically, we found that mice with the mutation emitted fewer vocalizations per unit time and had longer pauses between vocalizations and that the entropy of the temporal sequence was significantly reduced. Furthermore, Gnptab missense mice were similar to wild-type mice on an extensive battery of non-vocal behaviors. We then used the same language-agnostic metrics for auditory signal analysis of human speech. We analyzed speech from people who stutter with mutations in this pathway and compared it to control speech and found abnormalities similar to those found in the mouse vocalizations. These data show that mutations in the lysosomal enzyme-targeting pathway produce highly specific effects in mouse pup vocalizations and establish the mouse as an attractive model for studying this disorder.
一种理解言语机制基础的有前景的方法是研究那些影响言语但不损害其他认知或运动功能的疾病。口吃，也称为结巴，已与溶酶体酶靶向途径中的突变相关联，但这种非常特殊的言语缺陷如何由一系列一般的“细胞家务”基因中的突变产生尚不清楚。为了解决这个问题，我们询问与人类口吃相关的错义突变是否会在小鼠中导致发声或其他异常。我们比较了经基因工程改造携带Gnptab（N-乙酰葡糖胺-1-磷酸转移酶亚基α/β）基因突变的小鼠与野生型同窝小鼠的发声情况。我们发现携带人类Gnptab口吃突变的幼崽与同窝对照相比，发声存在显著差异。具体而言，我们发现突变小鼠每单位时间发出的叫声更少，叫声之间的停顿更长，并且时间序列的熵显著降低。此外，Gnptab错义突变小鼠在一系列广泛的非发声行为上与野生型小鼠相似。然后，我们使用相同的与语言无关的指标对人类言语进行听觉信号分析。我们分析了在该途径中存在突变的口吃者的言语，并将其与对照言语进行比较，发现了与小鼠发声中发现的异常相似的情况。这些数据表明，溶酶体酶靶向途径中的突变在小鼠幼崽发声中产生了高度特异性的影响，并将小鼠确立为研究这种疾病的有吸引力的模型。
