Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old Hsp^S139F mice. Though sphingolipid levels were not altered in sciatic nerves from Hsp^S139F mice, ceramides and deoxyceramides, as well as sphingomyelins (SMs) were elevated in brain tissues from Hsp^S139F mice. Histology was utilized to further characterize Hsp^S139F mice. Hsp^S139F mice exhibited no alterations to the expression and phosphorylation of neurofilaments, or in the expression of acetylated α-tubulin in the brain or sciatic nerve. Interestingly, Hsp^S139F mice demonstrated cerebellar demyelination. Locomotor function, grip strength and gait were examined to define the role of Hsp^S139F in the clinical phenotypes associated with CMT2F. Gait analysis revealed no differences between Hsp^WT and Hsp^S139F mice. However, both coordination and grip strength were decreased in 3-month-old Hsp^S139F mice. Together these data suggest that the endogenous S139F mutation in HSPB1 may serve as a mouse model for hereditary and sensory neuropathies such as CMT2F.

腓骨肌萎缩症 (CMT) 是一种常见的遗传性周围多发性神经病。这种疾病的临床表现包括对称性远端多发性神经病、深部腱反射改变、远端感觉丧失、足部畸形和步态异常。热休克蛋白的基因突变与 CMT2 相关。具体而言，编码热休克蛋白27 (Hsp27)的热休克蛋白B1 ( HSPB1 )基因的突变已与CMT2F和远端遗传性运动和感觉神经病2B型(dHMSN2B)亚型相关。该研究的目的是检查体内HSPB1 内源性突变的作用，并在新型动物模型中确定该突变对运动功能和病理学的影响。由于鞘脂与遗传性和感觉神经病有关，我们检查了3 个月大的 Hsp ^S139F小鼠中枢和周围神经组织中的鞘脂代谢。^{尽管 Hsp S139F}小鼠坐骨神经中的鞘脂水平没有改变，但^{Hsp S139F小鼠脑组织中的}神经酰胺和脱氧神经酰胺以及鞘磷脂 (SM) 有所升高。利用组织学进一步表征 Hsp ^S139F小鼠。Hsp ^S139F小鼠的神经丝表达和磷酸化，或大脑或坐骨神经中乙酰化 α-微管蛋白的表达没有变化。有趣的是，Hsp ^S139F小鼠表现出小脑脱髓鞘。^{检查运动功能、握力和步态，以确定 Hsp S139F}在与 CMT2F 相关的临床表型中的作用^{步态分析显示 Hsp WT}和 Hsp ^S139F小鼠之间没有差异。^{然而，3 个月大的 Hsp S139F}小鼠的协调性和握力均有所下降。这些数据共同表明，HSPB1 中的内源性 S139F 突变可以作为遗传性和感觉神经病（例如 CMT2F）的小鼠模型。