ArticleThe Journal of clinical investigation2020
Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Notch Signaling Regulates the Neuroprotective Effects of hUCMSCs in a Mouse Model of Cerebral Ischemia.Journal of molecular neuroscience : MN · 2026Article
- Improved functional JAG1 and NOTCH2 variant testing in patients with clinical or suspected Alagille syndrome using new low-Notch activity cells.Human genetics · 2026Article
- Postnatal development and form-function relationships of the vocal folds in California mice (American journal of physiology. Cell physiology · 2026Article
- Notch2 is involved in regulating apical tissue repair following severe intrusive luxation.Journal of applied oral science : revista FOB · 2026Article
- ProteinMolecules (Basel, Switzerland) · 2025Review
- Keratinocyte-Derived Exosomes in Painful Diabetic Neuropathy.bioRxiv : the preprint server for biology · 2024Article
- Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.Science translational medicine · 2024Article
- Article
- The Notch signaling pathway in skeletal muscle health and disease.Muscle & nerve · 2022Review
- Recognising the potential of large animals for modelling neuromuscular junction physiology and disease.Journal of anatomy · 2022Review
- A method to identify, dissect and stain equine neuromuscular junctions for morphological analysis.Journal of anatomy · 2022Article
- A form of muscular dystrophy associated with pathogenic variants in JAG2.American journal of human genetics · 2021Article
- The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve.Journal of neuroinflammation · 2021Review
- Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy.Neurobiology of pain (Cambridge, Mass.)Article
Corrections and comments
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Authors and funding
21 authors at 7 institutions in 2 countries.
Funding
Abstract
Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.