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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Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

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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Figure 2

Neuropathy-associated mutations affect conserved amino acids in the extracellular domain of JAG1.

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Neuropathy-associated mutations affect conserved amino acids in the extr...
(A) Clustal Omega alignments of the JAG1 protein from divergent species. The p.Ser577Arg and p.Ser650Pro mutations both disrupt serine residues located in highly conserved regions of JAG1. (B) The domain structure of JAG1, with the CMT2-associated mutations indicated in red. Though Alagille syndrome is primarily caused by JAG1 gene deletion or truncating mutations, a number of missense mutations (shown in black) have been described (see Supplemental Methods for references). Of the 42 amino acids mutated in Alagille syndrome, 20 are cysteine residues and none are serine residues; few occur in proximity to Ser577 and Ser650. (C) A schematic of 3 canonical EGF-like repeats is shown, along with 2 proposed models for JAG1 EGF-like repeats 9–11. In model 1, residues 562–585 are split between EGF-like repeats 9 and 10, including a potential disulfide bridge between residues 567 and 572 preceding the start of repeat 10. Model 1 requires 2 insertions, 1 before and 1 within repeat 10. In model 2, residues 562 to 585 are included as a single insertion in the second loop of EGF-like repeat 10. (D) 3D modeling shows that Ser577 and Ser650 may reside on the same surface of the JAG1 extracellular domain (model 2).