Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2—regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

中文翻译：

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单细胞 ADNP 预测人类肌肉疾病：小鼠敲低导致肌肉萎缩


活动依赖性神经保护蛋白（ADNP）突变与自闭症样 ADNP 综合征患者的认知功能障碍有关，这些患者还患有运动成熟延迟的问题。因此，我们假设 ADNP 在多种肌病中失调，局部 ADNP 肌肉缺乏会导致肌病，可以通过 ADNP 片段 NAP 治疗。在这里，单细胞转录组学确定ADNP是人类肌肉发育的主要成分。 ADNP转录物浓度进一步预测了多种人类肌肉疾病，其浓度与 ADNP 靶相互作用蛋白微管末端蛋白 1 (EB1) 呈负相关。回到雄性小鼠转录组单细胞水平的建模， Adnp mRNA 浓度与运动疾病以及性成熟基因转录物呈年龄依赖性相关，而表达Adnp的肢体肌肉细胞随着年龄的增长而显着减少。小鼠Adnp杂合缺陷表现出肌肉微管减少和肌球蛋白轻链 ( Myl2 ) 失调以及运动功能障碍。 Cas9 小鼠中成人腓肠肌 Adnp 的 CRISPR 敲除导致跑步机（雄性）和步态（雌性）功能障碍，这些功能障碍通过 ADNP 片段、微管相互作用、 Myl2调节、NAP (CP201) 治疗得到了特别改善。总而言之，我们的研究为多功能肌病的个性化诊断/治疗提供了新的希望。