, and Prdm12 (PRDM12) collaboratively participate in the promotion of nociceptor fate (Desiderio et al., 2019); correspondingly, pathogenic variations in these genes lead to autosomal recessive conditions with comparable symptoms, namely,HSAN V (MIM #608654), HSAN IV (CIPA), and HSAN VIII (MIM #616488). Within this study, the patient displayed typical CIPA manifestations which include multiple fractures, ankle swelling, intellectual delay, rachioscoliosis, and osteomyelitis. The subsequent WES detection identified the causative compound heterozygous NTRK1variation consisting of c.8513T A and c.2242C T (p. Arg748Trp) (NM_001012331). As we stated previously, the former variant can be a hotspot mutation in East Asian folks (Indo, 2001; Wang et al., 2017; Liu et al., 2018; Li et al., 2019; Zhao et al., 2020; Li et al., 2021); whereas the latter one is a novel missense variant. In line with the common interpretation guidelines supplied by ACMG (14), it was recognized as “uncertain significance” (with evidences of PM1+PM2+PP2+BP4). The BP4 evidence was resulting from the “uncertain” outcome by Revel and benign computational verdict by quite a few tools inside the Varsome predicting website (varsome. com/). As a result, additional investigation was essential to confirm the pathogenicity of this variant. The conservatism of Arg748 AA residue across species PLK4 Formulation indirectly suggested the pathogenicity of p. Arg748Trp variant. In addition to, in accordance with the structural modeling and MD simulation outcome, the p.Arg748Trp variant could possibly transform the conformation with the loop which the Arg748 belongs to (Bertrand et al., 2012). Therefore, the variant could possibly result in the structural instability of TrkA protein and further broke its binding to NGF. But, extra mechanistic experiments are needed to validate no matter if this variant could bring about loss of protein function. With regard to the in vitro study, we intended to analyze the cellular effect of NTRK1Arg748Trp variant in the perspective of metabolic modifications. It was demonstrated that the purine metabolism pathway was considerably affected. Furthermore, it seemed that the up-regulation of NT5C2 mRNA level must be a significant contribution to this effect. Duarte et al. demonstrated that NT5C2 could take part in the neural development and motility of Drosophila by regulating the AMPK signaling pathway (DuarteFrontiers in Genetics | frontiersin.orgDecember 2021 | Volume 12 | ArticleYang et al.Evaluation of a Novel NTRK1 Variationet al., 2019). Singgih et al. showed that impairment in cNT5-II (NT5C2 orthologs in Drosophila) resulted in disease-relevant behaviors in Drosophila. Novarino et al. revealed that NT5C2 mutations could result in a extreme neurodegenerative motor neuron illness, hereditary spastic paraplegia (Spastic paraplegia 45, MIM #613162) (Novarino et al., 2014), which was validated by other research (Darvish et al., 2017; Naseer et al., 2020). Collectively, it can be deduced that NT5C2 plays a important role in the development and mGluR1 list functional maintenance of neurosystem. Up to our information, the NGF/TrkA signaling could take part in the process of cell survival, proliferation, and migration through a minimum of three pathways, namely, RAS/RAF/MEK/ERK, PI3K/Akt, and PLC/ PCK (Thomaz et al., 2020; Esteban-Villarrubia et al., 2020). By way of in silico evaluation, we discovered that there had been multiple binding sites of transcriptional variables for instance STAT1, ELK1, and NF-B at the upstream promoter region of NT5C2 gene (Supplementary Material 1), and all these things ar
