Under the direction of Dr. Yotam Drier and Prof. Maayan Salton from Hebrew University’s Faculty of Medicine, MD-PhD candidate Eden Engal recently conducted a study that shed light on the development of facioscapulohumeral muscular dystrophy (FSHD). It highlighted the crucial role of the SMCHD1 protein in the regulation of alternative splicing. This complicated illness, which results in progressive muscle weakness and loss of function, is driven by genetic factors. The findings of the researchers advance our knowledge of the genetic processes underlying this debilitating disease.
Approximately 1 in 20,000 persons worldwide suffer from FSHD, one of the most prevalent types of muscular dystrophy. It is brought on by genetic abnormalities that enable the DUX4 gene in muscle cells to be inappropriately activated. This activation impairs normal muscle function and eventually leads muscle cells to degenerate. There is a vast range in the disease severity; some people have modest symptoms, while others may lose a large amount of muscular function and movement. For yet, there is no treatment for FSHD.
Splicing is the process by which portions of the genes are cut out of the RNA during the transcription of DNA into RNA. Alternative splicing is the term given to the process of producing distinct proteins from the same DNA by controlling which sections are deleted. This process is controlled by several proteins.
The latest research discovered that SMCHD1 has a significant impact on alternative splicing in addition to its well-known function in controlling chromosomal shape. It was previously recognized that FSHD and DUX4 expression were caused by mutations in the SMCHD1 gene, but it remained unclear how.
Comprehensive splicing mistakes in several genes due to lack of SMCHD1 were found in RNA sequencing data from muscle biopsies of FSHD patients and cells genetically engineered to lack SMCHD1. The splicing factor RBM5 was shown to be involved in these anomalies through a thorough screening of splicing factors, and additional testing verified that SMCHD1 is necessary for attracting RBM5 to its target RNA locations.