Sullivan, JM;
Motley, WW;
Johnson, JO;
Aisenberg, WH;
Marshall, KL;
Barwick, KES;
Kong, L;
... Sumner, CJ; + view all
(2020)
Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.
Journal of Clinical Investigation
, 130
(3)
pp. 1506-1512.
10.1172/JCI128152.
Preview |
Text
jci-130-128152_JAG1.pdf - Published Version Download (5MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/JCI128152 |
| Publisher version: | https://doi.org/10.1172/JCI128152 |
| Language: | English |
| Additional information: | This version is the version of record. For information on re-use, please refer to the publisher's terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107404 |
Archive Staff Only
 |
View Item |
