Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

Abstract

Authorship note: JMS and WWM are co-first authors. Conflict of interest: WWM is currently an employee of Third Rock Ventures. JOJ is currently an employee of Quest Diagnostics. BJT has received grant support from Merck and Microsoft Research. BJT holds European Union (EP2751284A1, Method For Diagnosing A Neurodegenerative Disease) and US (20180187262) patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of the C9orf72 gene. CJS has received grant support from and holds patents (WO2016/164896 "Modulation of SMN expression," WO2017/21884 "Combinations for the Modulation of SMN expression") with Ionis Pharmaceuticals; has served as a paid advisor, consultant, and/or speaker for Biogen, PTC Therapeutics, Roche/Genentech, AveXis, and Cytokinetics; and is an associate editor for the JCI. This arrangement has been approved by Johns Hopkins University in accordance with its conflict of interest policies.

A form of muscular dystrophy associated with pathogenic variants in JAG2

“…9 Dominant, heterozygous truncating, or missense mutations in Notch ligands can cause severe congenital disorders, including the JAG1-associated Alagille syndrome 1 (AGS [MIM: 118450]); tetralogy of Fallot (TOF [MIM: 187500]); deafness, congenital heart defects, and posterior embryotoxon (DCHE [MIM: 617992]); peripheral neuropathy; DLL1-associated neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures (NEDBAS [MIM: 618709]); and DLL4associated Adams-Oliver syndrome 6 (AOS6 [MIM: 616589]). [10][11][12][13][14][15] The DLL3-associated autosomal recessive spondylocostal dysostosis (SCDO1 [MIM: 277300]) is caused by bi-allelic DLL3 pathogenic variants. 16 JAG2 is located at chromosomal region 14q32.33, comprises 26 exons, and is constrained for predicted loss-of-function (pLoF) variants in the gnomAD.…”

The influence of BACE1 on macrophage recruitment and activity in the injured peripheral nerve

“…There is increasing evidence of the importance of Notch signaling through its ligand Jag1 in the context of the peripheral nerve disorders. Mutations in Jag1 have been associated with peripheral neuropathy in humans [ 83 ]. Transgenic mice bearing the same mutations in Jag1 as affected patients display abnormal focally folded myelin [ 83 ].…”

“…Mutations in Jag1 have been associated with peripheral neuropathy in humans [ 83 ]. Transgenic mice bearing the same mutations in Jag1 as affected patients display abnormal focally folded myelin [ 83 ]. More broadly, Notch signaling has been shown to play a role in the regulation of Schwann cells and post-natal myelination [ 84 ].…”

“…Given the abundance of Notch receptors and Notch ligands, it is unlikely that BACE1 would have absolute regulatory control over any of these effects, but rather it could be a crucial mediator that helps tip the balance of signaling towards a pro-regenerative phenotype in the peripheral nerve. The link between mutations in Jag1 and peripheral neuropathies [ 83 ] also highlights an interesting avenue of clinically significant research to pursue in the future.…”

Dystrophie musculaire liée à des mutations du gène JAG2

“…Les immunomarquages des protéines membranaires sont normaux hormis un CAS CLINIQUE nerveux central (SNC) (mutations dominantes de DLL1) [8][9][10][11], au syndrome CADASIL consécutif aux mutations du gène NOTCH3 (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) [14], ainsi qu'au syndrome de dysostose spondylocostale (mutations récessives du gène DLL3) [12]. Par ailleurs, des mutations du gène JAG1 ont été également associées à des neuropathies périphériques héréditaires avec atteinte des cordes vocales [13]. Concernant la dystrophie musculaire liée au gène JAG2, le début des symptômes est variable, s'étendant de la petite enfance à l'adolescence.…”