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Citations to this article

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy
Jeremy M. Sullivan, … , Andrew H. Crosby, Charlotte J. Sumner
Jeremy M. Sullivan, … , Andrew H. Crosby, Charlotte J. Sumner
Published February 17, 2020
Citation Information: J Clin Invest. 2020;130(3):1506-1512. https://doi.org/10.1172/JCI128152.
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Concise Communication Genetics Neuroscience Article has an altmetric score of 5

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

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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.

Authors

Jeremy M. Sullivan, William W. Motley, Janel O. Johnson, William H. Aisenberg, Katherine L. Marshall, Katy E.S. Barwick, Lingling Kong, Jennifer S. Huh, Pamela C. Saavedra-Rivera, Meriel M. McEntagart, Marie-Helene Marion, Lucy A. Hicklin, Hamid Modarres, Emma L. Baple, Mohamed H. Farah, Aamir R. Zuberi, Cathleen M. Lutz, Rachelle Gaudet, Bryan J. Traynor, Andrew H. Crosby, Charlotte J. Sumner

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Total citations by year

Year: 2025 2024 2023 2022 2021 Total
Citations: 1 3 1 4 2 11
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Citations to this article (11)

Title and authors Publication Year
Protein O-Fucosyltransferases: Biological Functions and Molecular Mechanisms in Mammals
Hao H, Eberand BM, Larance M, Haltiwanger RS
Molecules 2025
Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice
Sullivan JM, Bagnell AM, Alevy J, Avila EM, Mihaljević L, Saavedra-Rivera PC, Kong L, Huh JS, McCray BA, Aisenberg WH, Zuberi AR, Bogdanik L, Lutz CM, Qiu Z, Quinlan KA, Searson PC, Sumner CJ
Science Translational Medicine 2024
Keratinocyte-Derived Exosomes in Painful Diabetic Neuropathy
Coy-Dibley J, Jayaraj ND, Ren D, Pacifico P, Belmadani A, Wang YZ, Gebis KK, Savas JN, Paller AS, Miller RJ, Menichella DM
bioRxiv 2024
Keratinocyte-derived extracellular vesicles in painful diabetic neuropathy
Coy-Dibley J, Jayaraj ND, Ren D, Pacifico P, Belmadani A, Wang YZ, Gebis KK, Savas JN, Paller AS, Miller RJ, Menichella DM
Neurobiology of Pain 2024
Genome-wide analysis reveals novel regulators of synaptic maintenance in Drosophila
Sidisky JM, de Paula Moreira D, Okumus M, Caratenuto R, Drost C, Connors B, Hussain S, Alkhatib S, Babcock DT
Genetics 2023
Clinical genetics of Charcot–Marie–Tooth disease
Y Higuchi, H Takashima
Journal of Human Genetics 2022
Recognising the potential of large animals for modelling neuromuscular junction physiology and disease
Cahalan SD, Boehm I, Jones RA, Piercy RJ
Journal of Anatomy 2022
A method to identify, dissect and stain equine neuromuscular junctions for morphological analysis
Cahalan SD, Perkins JD, Boehm I, Jones RA, Gillingwater TH, Piercy RJ
Journal of Anatomy 2022
The Notch signaling pathway in skeletal muscle health and disease.
Vargas-Franco D, Kalra R, Draper I, Pacak CA, Asakura A, Kang PB
Muscle & Nerve 2022
The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve
JA Fissel, MH Farah
Journal of Neuroinflammation 2021
A form of muscular dystrophy associated with pathogenic variants in JAG2
S Coppens, AM Barnard, S Puusepp, S Pajusalu, K Õunap, D Vargas-Franco, CC Bruels, S Donkervoort, L Pais, KR Chao, JK Goodrich, EM England, B Weisburd, VS Ganesh, S Gudmundsson, A ODonnell-Luria, M Nigul, P Ilves, P Mohassel, T Siddique, M Milone, S Nicolau, R Maroofian, H Houlden, MG Hanna, R Quinlivan, MB Toosi, EG Karimiani, S Costagliola, N Deconinck, H Kadhim, E Macke, BC Lanpher, EW Klee, A Łusakowska, A Kostera-Pruszczyk, A Hahn, B Schrank, I Nishino, M Ogasawara, RE Sherif, T Stojkovic, I Nelson, G Bonne, E Cohen, A Boland-Augé, JF Deleuze, Y Meng, A Töpf, C Vilain, CA Pacak, ML Rivera-Zengotita, CG Bönnemann, V Straub, PA Handford, I Draper, GA Walter, PB Kang
The American Journal of Human Genetics 2021

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