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Abstract：
Congenital insensitivity to pain is a rare human condition in which affected individuals do not experience pain throughout their lives. This study aimed to identify the molecular etiology of congenital insensitivity to pain in two Thai patients. Clinical, radiographic, histopathologic, immunohistochemical, and molecular studies were performed. Patients were found to have congenital insensitivity to pain, self-mutilation, acro-osteolysis, cornea scars, reduced temperature sensation, tooth agenesis, root maldevelopment, and underdeveloped maxilla and mandible. The skin biopsies revealed fewer axons, decreased vimentin expression, and absent neurofilament expression, indicating lack of dermal nerves. Whole exome and Sanger sequencing identified a rare homozygous variant c.4039C>T; p.Arg1347Cys in the plakin domain of Plec, a cytolinker protein. This p.Arg1347Cys variant is in the spectrin repeat 9 region of the plakin domain, a region not previously found to harbor pathogenic missense variants in other plectinopathies. The substitution with a cysteine is expected to decrease the stability of the spectrin repeat 9 unit of the plakin domain. Whole mount in situ hybridization and an immunohistochemical study suggested that Plec is important for the development of maxilla and mandible, cornea, and distal phalanges. Additionally, the presence of dental anomalies in these patients further supports the potential involvement of Plec in tooth development. This is the first report showing the association between the Plec variant and congenital insensitivity to pain in humans.
摘要：
先天性对疼痛不敏感是一种罕见的人类疾病，其中受影响的个体一生都不会经历疼痛。这项研究旨在确定两名泰国患者对疼痛先天性不敏感的分子病因。临床,射线照相,组织病理学,免疫组织化学，并进行了分子研究。患者被发现对疼痛有先天性不敏感，自残,肢端骨溶解,角膜疤痕,降低温度的感觉，牙齿发育不全,根发育不良，上颌骨和下颌骨发育不全。皮肤活检显示轴突较少，波形蛋白表达减少，缺乏神经丝表达，说明皮肤神经缺乏.全外显子组和Sanger测序确定了一个罕见的纯合变体c.4039C>T;p.Arg1347Cys在Plec的plakin域中，一种细胞蛋白。这个p.Arg1347Cys变体位于plakin结构域的spectrin重复9区域,以前没有发现在其他plectinopathies中存在致病性错义变异的区域。预期用半胱氨酸取代会降低plakin结构域的spectrin重复9单元的稳定性。整体原位杂交和免疫组织化学研究表明，Plec对上颌骨和下颌骨的发育很重要，角膜,和远端指骨。此外,这些患者中牙齿异常的存在进一步支持了Plec可能参与牙齿发育。这是第一份报告，显示了Plec变异与人类对疼痛的先天性不敏感之间的关联。
