A mutation in a previously unexamined Notch ligand, JAG2, is found to cause a rare form of muscular dystrophy (MD) that is consistent across multiple countries and ethnic groups. It has a distinct pattern on muscle MRI that could be used for future diagnosis.
In this recent study, 23 individuals from 13 families were investigated as having genetically unsolved MD and were found to have a variety of mutations in the Notch ligand gene, JAG2.
Muscular dystrophies are a group of genetic conditions that lead to progressive muscle weakening. There are over 60 different muscle-wasting diseases, affecting just over 1 in 1,000 people and is considered a rare disease. The most common types of MD are Myotonic, Duchenne, Becker and Limb-Girdle.
The Notch signalling pathway is a highly conserved cell-cell communication system that is involved in many processes, from determining embryonic differentiation to heart development. This pathway involves several ligands as Notch is a transmembrane protein that protrudes from the cell – allowing connections to neighbouring cells via ligands. One of these ligands is Jagged2, which is involved in limb development and encoded by the gene JAG2.
However, JAG2 has not previously been associated with a disease. Many other mutations in Notch ligands do cause disease, from congenital heart defects to neurodevelopmental disorders.
This international cohort of 23 people from 13 families consisted of 12 males and 11 females. Six of the families were consanguineous. As mentioned, these individuals had genetically unsolved MD and a wide range of symptom severity – but all had progressive muscle weakness, most notable in the proximal muscles.
Whole exome sequencing was performed on all participants and fifteen different JAG2 mutations were found. Ten were missense, 2 frameshifts, 1 nonsense, 1 in-frame deletion and a larger deletion that encompassed JAG2.
Transcriptome analysis on muscle tissue from 2 participants was performed. Researchers found that myogenesis was misregulated, with lower RNA levels of MYF5 and PAXJ. More importantly, the results from the muscle MRI identified a distinct pattern that could be used to identify future patients.
JAG2 is less sensitive to gene dosage than other components of the Notch signalling pathway. Many of the parents in the cohort (who had heterozygous loss-of-function variants) were unaffected. This is not the case for other Notch ligands.
Examining the interactions between Jagged2 and the Notch signalling pathway opens an opportunity for novel treatments for MD. This study also increases the likelihood that more patients will be correctly diagnosed by including JAG2 in genetic testing panels and through muscle MRI.