Exploring gene activity to understand symptoms and severity in Sanfilippo and Morquio disease

07 Mar 2022

Researchers have sought to get a better understanding of the biology that lies behind the variation in symptoms and severity in different types and subtypes of mucopolysaccharidosis (MPS) diseases, by investigating the genes that are switched on and off in patients with these conditions.

Sanfilippo syndrome (MPS III) and Morquio syndrome (MPS IV) are unique as they are the only forms of MPS to have different subtypes caused by mutations in different genes: there are four subtypes of Sanfilippo (types A, B, C, and D) and two subtypes of Morquio (types A and B).

While they share these similarities, Sanfilippo and Morquio present as very different diseases. Individuals with Sanfilippo experience severe neurological symptoms and develop dementia. Individuals with Morquio syndrome usually do not experience neurological symptoms but skeletal development is severely affected. While there can be a wide variation in disease severity between Sanfilippo subtypes, and even between patients with the same subtype, Morquio types A and B can appear very similar, though patients with type B may have milder symptoms.

Researchers from the University of Gdansk in Poland recently published the results of their study comparing the activity of genes in skin cells of patients with all subtypes of Sanfilippo and Morquio. They used a powerful technique called RNA-seq analysis, which allows researchers to look at all of the genes that are either switched on or switched off in cells and tissues.

The study identified greater variation in the activity of different genes between the Sanfilippo subtypes. This indicates that there is more diversity in the biological effects of the subtypes at the molecular level between Sanfilippo types A-D. There was much less variation in gene products between Morquio types A and B, possibly helping to explain why Morquio syndrome subtypes appear much more similar compared to the subtypes of Sanfilippo.

Gene products that varied the most between Sanfilippo and Morquio cells included those involved in protein production, cellular signalling, and the structure of connective tissue (e.g. bone, cartilage, and collagen-producing cells). The researchers propose that altered gene products arising due to the respective diseases may contribute to further cellular changes, helping to drive the disease and leading to variations in the disease trajectory.

When the Sanfilippo subtypes were directly compared, it was found types A and B had a greater number of extreme changes in gene activity levels compared to types C and D cells. For example, the Sanfilippo type A cells showed reduced gene products for the gene RPL10 compared with types C and D. Changes in the activity of the RPL10 gene have also been implicated in autism spectrum disorder. The authors speculate that reduced RPL10 gene activity may contribute to the higher prevalence of autism-like symptoms seen in Sanfilippo type A.

As the researchers found hundreds of changes in gene products between disease cells and unaffected (non-MPS) cells, they suggest most of the changes are related to the disease, and not due to natural variation between individual patients. However, only one cell line for each of the Sanfilippo and Morquio subtypes was used in the study and analysis of further samples will be needed to paint a more accurate picture of the genetic changes associated with subtypes of these diseases.

This study highlights the importance of comparing different diseases like Sanfilippo and Morquio. By investigating the different MPS diseases together, it is possible to discover aspects of each disease that can help to understand MPS diseases collectively.

The study was funded by the National Science Center, Poland, and with a grant from the University of Gdansk.