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

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 4

Homozygous expression of the JAG1S577R mutation causes embryonic lethality in mice, while heterozygous expression results in mild peripheral neuropathy.

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Homozygous expression of the JAG1S577R mutation causes embryonic lethali...
(A and B) Genotyping of postnatal (A) and embryonic (B; E8.5–E12.5) mice generated from heterozygous intercrosses demonstrates embryonic lethality in Jag1S577R/S577R mice. (C–F) Jag1S577R/+ mice display impaired performance in the inverted grid test (C) as well as reductions in CMAP area (D and E), but not latency (F). Representative CMAP traces are shown in D. n = 11 for WT; n = 19 for Jag1S577R/+. *P < 0.05; **P < 0.01, 2-tailed Student’s t test. (G and H) TEM reconstructions of the recurrent laryngeal nerve of WT (G) and Jag1S577R/+ (H) mice. Insets show higher magnification images of individual myelinated axons. Scale bars: 10 μm; 2 μm (insets). Arrowheads indicate regions of focally folded myelin (15). (I–K) Myelinated axons in the recurrent laryngeal nerve of Jag1S577R/+ mice exhibit normal g-ratios (I) and numbers of actively degenerating axons (J), but an increased incidence of focally folded myelin (K) For I, n = 350 axons from 3 WT mice; n = 410 axons from 3 Jag1S577R/+ mice. For J and K, n = 3 for WT and Jag1S577R/+. *P < 0.05, 2-tailed Student’s t test.