ArticleThe Journal of biological chemistry2016
Mutations in TrkA Causing Congenital Insensitivity to Pain with Anhidrosis (CIPA) Induce Misfolding, Aggregation, and Mutation-dependent Neurodegeneration by Dysfunction of the Autophagic Flux.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
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- Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-Type Non-Small Cell Lung Cancer.Cancer research · 2024Article
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- NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway.Cell death discovery · 2023Article
- Molecular Mechanisms of RSV and Air Pollution Interaction: A Scoping Review.International journal of molecular sciences · 2022Article
- Next Steps in Prader-Willi Syndrome Research: On the Relationship between Genotype and Phenotype.International journal of molecular sciences · 2022Review
- Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (International journal of molecular sciences · 2022Article
- Identification of novel variations in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis.Molecular genetics & genomic medicine · 2021Article
- The development of somatosensory neurons: Insights into pain and itch.Current topics in developmental biology · 2021Review
- Clinical, genomics and networking analyses of a high-altitude native American Ecuadorian patient with congenital insensitivity to pain with anhidrosis: a case report.BMC medical genomics · 2020Article
- Hypothesis: determining phenotypic specificity facilitates understanding of pathophysiology in rare genetic disorders.Journal of inherited metabolic disease · 2020Article
- Tetraspanin1 promotes NGF signaling by controlling TrkA receptor proteostasis.Cellular and molecular life sciences : CMLS · 2020Article
- Understanding the genetic basis of congenital insensitivity to pain.British medical bulletin · 2020Review
- Heterogeneity of clinical features and mutation analysis ofJournal of pain research · 2019Article
- Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy.Physiological reports · 2017Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager. We found that TrkA mutations induce misfolding, retention in the endoplasmic reticulum (ER), and aggregation in a mutation-dependent manner. The distinct mutations are degraded with a different kinetics by different ER quality control mechanisms; although C300stop is rapidly disposed by autophagy, Δ736 degradation is sensitive to the proteasome and to autophagy inhibitors, and L213P is a long-lived protein refractory to degradation. In addition L213P enhances the formation of autophagic vesicles triggering an increase in the autophagic flux with deleterious consequences. Mouse cortical neurons expressing L213P showed the accumulation of LC3-GFP positive puncta and dystrophic neurites. Our data suggest that TrkA misfolding and aggregation induced by some CIPA mutations disrupt the autophagy homeostasis causing neurodegeneration. We propose that distinct disease-causing mutations of TrkA generate different levels of cell toxicity, which may provide an explanation of the variable intellectual disability observed in CIPA patients.
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