Abstract
Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.
Highlights
Reviewed by: Jesus Delgado-Calle, University of Arkansas for Medical Sciences, United States Sandesh Nagamani, Baylor College of Medicine, United States
The pathogenic variants associated with Lateral Meningocele Syndrome (LMS) are analogous to those reported in Hajdu Cheney Syndrome (HCS), a genetic disorder caused by pathogenic variants in exon 34 of NOTCH2 resulting in the translation of a truncated NOTCH2 protein lacking the PEST domain and a gain-of-NOTCH2 function (Isidor et al, 2011; Simpson et al, 2011; Canalis and Zanotti, 2014; Canalis, 2018)
We introduced the described human NOTCH3 pathogenic variant into the mouse genome creating a tandem stop codon (6691-6696 ACCAAG>TAATGA), which would lead to a T2231X change at the amino acid level and a NOTCH3 protein of 2,230 amino acids lacking the PEST domain
Summary
Department of Orthopaedic Surgery and Medicine, UConn Musculoskeletal Institute, UConn Health, Farmington, CT, United States Edited by: Roy Morello, University of Arkansas for Medical Sciences, United States Reviewed by: Jesus Delgado-Calle, University of Arkansas for Medical Sciences, United States Sandesh Nagamani, Baylor College of Medicine, United States
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