Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.
Document Type
Article
Publication Date
3-2-2020
Keywords
JMG
JAX Source
J Clin Invest 2020 Mar 2; 130(3):1506-1512
Volume
130
Issue
3
First Page
1506
Last Page
1512
ISSN
1558-8238
PMID
32065591
DOI
https://doi.org/10.1172/JCI128152
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.
Recommended Citation
Sullivan J,
Motley W,
Johnson J,
Aisenberg W,
Marshall K,
Barwick K,
Kong L,
Huh J,
Saavedra-Rivera P,
McEntagart M,
Marion M,
Hicklin L,
Modarres H,
Baple E,
Farah M,
Zuberi A,
Lutz C,
Gaudet R,
Traynor B,
Crosby A,
Sumner C.
Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy. J Clin Invest 2020 Mar 2; 130(3):1506-1512