The R100W mutation in nerve growth factor is associated with hereditary sensory autonomic neuropathy V in a Swedish family. These patients develop severe loss of perception to deep pain but with apparently normal cognitive functions. To better understand the disease mechanism, we examined a knockin mouse model of HSAN V. The homozygous mice showed significant structural deficits in intra-epidermal nerve fibers (IENFs) at birth. These mice had a total loss of pain perception at ∼2 months of age and often failed to survive to adulthood. Heterozygous mutant mice developed a progressive degeneration of small sensory fibers both behaviorally and functionally: they showed a progressive loss of IENFs starting at the age of 9 months accompanied with progressive loss of perception to painful stimuli such as noxious temperature. Quantitative analysis of lumbar 4/5 dorsal root ganglia revealed a significant reduction in small size neurons, while analysis of sciatic nerve fibers revealed the heterozygous mutant mice had no reduction in myelinated nerve fibers. Significantly, the amount of NGF secreted from mouse embryonic fibroblasts were reduced from both heterozygous and homozygous mice compared to their wild-type littermates. Interestingly, the heterozygous mice showed no apparent structural alteration in the brain: neither the anterior cingulate cortex nor the medial septum including NGF-dependent basal forebrain cholinergic neurons. Accordingly, these animals did not develop appreciable deficits in tests for brain function. Our study has thus demonstrated that the NGF^R100W mutation likely affects the structure and function of peripheral sensory neurons.

神经生长因子 R100W 突变与瑞典家族遗传性感觉自主神经病 V 相关。这些患者对深部疼痛的知觉严重丧失，但认知功能明显正常。为了更好地了解疾病机制，我们检查了 HSAN V 的敲入小鼠模型。纯合小鼠在出生时表现出表皮内神经纤维 (IENF) 的显着结构缺陷。这些小鼠在大约 2 个月大时就完全丧失了疼痛知觉，并且常常无法存活到成年。杂合突变小鼠在行为和功能上都出现了小感觉纤维的进行性退化：它们从 9 个月大开始就表现出 IENF 的逐渐丧失，并伴随着对有害温度等疼痛刺激的知觉逐渐丧失。腰椎4/5背根神经节的定量分析显示小尺寸神经元显着减少，而坐骨神经纤维的分析显示杂合突变小鼠的有髓神经纤维没有减少。值得注意的是，与野生型同窝小鼠相比，杂合子和纯合子小鼠胚胎成纤维细胞分泌的 NGF 量均减少。有趣的是，杂合子小鼠的大脑没有表现出明显的结构改变：前扣带皮层和内侧隔膜（包括 NGF 依赖性基底前脑胆碱能神经元）都没有改变。因此，这些动物在脑功能测试中没有出现明显的缺陷。因此，我们的研究证明 NGF ^R100W突变可能影响周围感觉神经元的结构和功能。