Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders of the peripheral nervous system. CMT is subdivided into two main types: a demyelinating form, known as CMT1, and an axonal form, known as CMT2. Nearly 30 genes have been identified as a cause of CMT2. One of these is the 'dehydrogenase E1 and transketolase domain containing 1' (DHTKD1) gene. We previously demonstrated that a nonsense mutation [c.1455 T > G (p.Y485*)] in exon 8 of DHTKD1 is one of the disease-causing mutations in CMT2Q (MIM 615025). The aim of the current study was to investigate whether human disease-causing mutations in the Dhtkd1 gene cause CMT2Q phenotypes in a mouse model in order to investigate the physiological function and pathogenic mechanisms associated with mutations in the Dhtkd1 gene in vivo. Therefore, we generated a knock-in mouse model with the Dhtkd1Y486* point mutation. We observed that the Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice. Moreover, a histopathological phenotype was observed, reminiscent of a peripheral neuropathy, including reduced large axon diameter and abnormal myelination in peripheral nerves. The knock-in mice also displayed clear sensory defects, while no abnormalities in the motor performance were observed. In addition, accumulation of mitochondria and an elevated energy metabolic state was observed in the knock-in mice. Taken together, our study indicates that the Dhtkd1Y486* knock-in mice partially recapitulate the clinical phenotypes of CMT2Q patients and we hypothesize that there might be a compensatory effect from the elevated metabolic state in the knock-in mice that enables them to maintain their normal locomotor function.

中文翻译：

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在敲入小鼠模型中，Dhtkd1基因中引起CMT2Q的突变导致感觉缺陷，线粒体积累和代谢改变。

Charcot-Marie-Tooth病（CMT）是一组周围神经系统的遗传性神经系统疾病。CMT分为两种主要类型：脱髓鞘形式（称为CMT1）和轴突形式（称为CMT2）。已经鉴定出将近30个基因引起CMT2。其中之一是“含1的脱氢酶E1和转酮酶结构域”（DHTKD1）基因。我们先前证明，DHTKD1外显子8中的无意义突变[c.1455 T> G（p.Y485 *）]是CMT2Q（MIM 615025）的致病突变之一。本研究的目的是研究Dhtkd1基因中人类致病的突变是否引起小鼠模型中的CMT2Q表型，以研究与Dhtkd1基因突变相关的体内生理功能和致病机制。因此，我们生成了具有Dhtkd1Y486 *点突变的敲入小鼠模型。我们观察到，敲入小鼠的坐骨神经中的Dhtkd1表达水平明显低于野生型小鼠。此外，观察到组织病理学表型，使人联想到周围神经病变，包括减少的大轴突直径和周围神经的异常髓鞘形成。敲入的小鼠也显示出明显的感觉缺陷，而没有观察到运动表现异常。另外，在敲入的小鼠中观察到线粒体的积累和能量代谢状态的升高。在一起