Health Canada (Commonwealth Union) – A team of researchers led by McGill has uncovered a significant breakthrough in understanding the genetic underpinnings of a rare skeletal disorder. Their findings, published in Nature Communications, highlight that a specific gene defect (heterozygous variants in the matrix Gla protein, or MGP) may be responsible for a disorder impacting the structural integrity of connective tissues that support the body.
Researchers of the study pointed out that MGP, a distinctive protein found in blood vessels and cartilage, plays a crucial role in preventing the hardening of these tissues. Complete absence of MGP can result in Keutel syndrome, a rare condition characterized by calcification of tissues, leading to complications in the skeletal and vascular systems.
In this study, the researchers observed a variation in the MGP gene that differs from Keutel syndrome, both in its clinical manifestation in individuals and the underlying cellular and molecular processes.
In the realm of rare genetic disorders, Keutel Syndrome stands as a distinctive and fascinating condition, offering insights into the delicate balance that governs human development. Named after the Dutch pediatrician, A.C. Keutel, who first described the syndrome in the 1970s, Keutel Syndrome is characterized by abnormal calcification of tissues, leading to a spectrum of skeletal and vascular abnormalities.
Keutel Syndrome is diagnosed based on a combination of clinical features and genetic testing. Individuals with this syndrome often exhibit facial abnormalities, such as a flat facial profile, a broad nasal bridge, and a short neck. The calcification of cartilage can result in hearing loss due to abnormalities in the middle ear. Respiratory issues may also arise due to tracheal calcification. Additionally, individuals with Keutel Syndrome may have cardiovascular abnormalities, contributing to the complexity of the disorder. Keutel Syndrome, though rare, serves as a poignant example of the intricate interplay between genetics and human development.
“Our paper reports four people from two different families who had a slight change in their MGP gene. These changes made the protein a bit different, and these individuals showed a specific bone disorder,” said Monzur Murshed, Full Professor in the Department of Medicine, Divisions of Endocrinology and Metabolism and Experimental Medicine as well as the Faculty of Dental Medicine and Oral Health Sciences, he is also the lead author of the study.
Following experimentation with these genetic modifications on mice to gain insights into the cellular and molecular dynamics, the researchers observed that the altered MGP induced similar bone issues in both mice and humans. In contrast to the normal protein, the modified version fails to exit the cells, leading to stress within the endoplasmic reticulum, a cellular component. The cartilage cells producing the modified protein are unable to withstand the stress, ultimately resulting in cell death and contributing to the observed bone abnormalities.
Researchers of the study further emphasized that when taking a significant step forward in comprehending rare diseases, this research not only enhances our understanding of the genetic elements influencing skeletal dysplasia but also opens avenues for potential therapeutic interventions. The study underscores the pivotal role of the MGP gene in skeletal development, offering prospects for improved diagnosis and treatment for individuals affected by this uncommon condition.
“There are many rare diseases with similar skeletal problems. We are hopeful that if more people are familiar with our work, they may come forward to consult with the clinicians and researchers,” said Professor Murshed. “After the publication of our paper last month, we have been contacted by a clinician who has examined another individual with skeletal dysplasia carrying the same mutation in the MGP gene. This may help further research and also improve the treatment and management of these diseases in the long run.”
