Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain with Anhidrosis (CIPA)

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused<br>mainly by bi-allelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.<br>Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation.<br>Subsequently, an in silico molecular dynamic(MD) analysis was performed to explore the intramolecular impact of the novel variant.<br>Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid<br>chromatography-mass spectrometry(LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).<br>Results: A novel compound heterozygous variation in NTRK1(NM_001012331) was detected, consisting of the c.851-33T&gt;A and<br>c.2242C&gt;T(p.Arg748Trp) variants. MD results suggested that p.Arg748Trp could impact the molecular structure stability. Results of<br>the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine<br>metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA.<br>Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected<br>family, and offered potential clues and biomarkers to the pathogenesis of CIPA. <br>