Cyclin-dependent–like kinase 5 (CDKL5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay, and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)–derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of CDKL5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)–dependent signaling, which are disrupted in both CDKL5 mutant murine DRG and human iPS–derived nociceptors. Together, these findings unveil a previously unrecognized role for CDKL5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

细胞周期蛋白依赖性样激酶 5 ( CDKL5 ) 基因突变导致 X 连锁疾病，其特征是婴儿癫痫性脑病、发育迟缓和肌张力减退。然而，我们发现这些患者中有很大一部分还报告了以前未被识别的疼痛感知记忆缺失。与伤害感受中的作用一致，我们发现 CDKL5 在小鼠的伤害性背根神经节 (DRG) 神经元和诱导多能干细胞 (iPS) 衍生的人类伤害感受器中选择性表达。CDKL5缺陷小鼠表现出表皮神经支配缺陷和CDKL5的条件缺失在背根神经节感觉神经元损害伤害感受，在患者中表现出 CDKL5 缺乏症。从机制上讲，CDKL5 与钙/钙调蛋白依赖性蛋白激酶 II α (CaMKIIα) 相互作用以控制生长和瞬时受体电位阳离子通道亚家族 V 成员 1 (TRPV1) 依赖性信号传导，这些信号传导在CDKL5突变小鼠 DRG 和人类 iPS中均被破坏–衍生伤害感受器。总之，这些发现揭示了 CDKL5 在伤害感受中以前未被认识的作用，提出了一种原始的疼痛感知调节机制，对 CDKL5 缺乏症的未来治疗有影响。