Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

J Clin Invest. 2020 Mar 2;130(3):1506-1512. doi: 10.1172/JCI128152.

Jeremy M Sullivan ¹, William W Motley ¹, Janel O Johnson ², William H Aisenberg ¹, Katherine L Marshall ¹, Katy Es Barwick ³, Lingling Kong ¹, Jennifer S Huh ¹, Pamela C Saavedra-Rivera ¹, Meriel M McEntagart ⁴, Marie-Helene Marion ⁵, Lucy A Hicklin ⁶, Hamid Modarres ⁵, Emma L Baple ³, Mohamed H Farah ¹ ⁷, Aamir R Zuberi ⁸, Cathleen M Lutz ⁸, Rachelle Gaudet ⁹, Bryan J Traynor ² ¹⁰, Andrew H Crosby ³, Charlotte J Sumner ¹ ⁷

Affiliations

1 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2 Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, Maryland, USA.
3 RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, United Kingdom.
4 Medical Genetics, Clinical Developmental Sciences, St. George's University of London, London, United Kingdom.
5 Department of Neurology and.
6 Department of Ears, Nose and Throat (ENT), St. George's Hospital, London, United Kingdom.
7 Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
8 Genetic Resource Science, The Jackson Laboratory, Bar Harbor, Maine, USA.
9 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.
10 Brain Sciences Institute, Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland, USA.

PMID: 32065591 DOI: 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.

Keywords

Genetic diseases; Genetics; Neurodegeneration; Neuromuscular disease; Neuroscience.

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