Researchers Pinpoint Cause of Rare Genetic Disorder

Researchers Pinpoint Cause of Rare Genetic Disorder

A team of international researchers is in the spotlight after pinpointing the cause of Singleton-Merten Syndrome (SMS), a rare inherited disorder with devastating health consequences, including life-threatening calcification of the aorta and heart valves; early-onset periodontitis and root resorption of the teeth; and bone tissue loss at the tips of fingers and toes. The global research team led by Mary MacDougall, PhD, of the University of Alabama at Birmingham (UAB), and Frank Rutsch, MD, of Münster University Children’s Hospital in Germany, revealed that SMS is caused by a mutation that changes a single amino acid in the protein MDA5 from arginine to glutamine. The data were presented in the online article, “A Specific IFIH1 Gain-of-Function Mutation Causes Singleton-Merten Syndrome,” published by the American Journal of Human Genetics. The finding is noteworthy; researchers have been investigating the mechanisms of this syndrome for more than 10 years—taking particular interest in the molecular basis and mechanisms associated with human dental genetic disorders that impact tooth number, formation, and hard tissue structure.

In examining the mechanisms of SMS, the research team discovered that the change in MDA5 protein initiated the creation of the cytokine interferon beta. This finding enabled SMS to become recognized as an autoimmune disease for the first time.

In 1995, Rutsch reached out to MacDougall, known internationally for her research in craniofacial developmental biology and dental genetics, after noticing unusual dental problems in his patients with SMS. For the study, three SMS-affected families agreed to undergo testing to identify the mutation, from which a single mutation was found in 10 patients. MacDougall and her team then analyzed the participants’ dental features, as well as dental pulp cell lines extracted from their third molars.

The analysis revealed that the presence of the SMS-IFIH1 mutant gene increased interferon beta gene expression twentyfold. IFIH1 has been linked to several other autoimmune disorders. MacDougall and her team at UAB will continue SMS-gene research, including its dysregulation of 30 genes involved in tooth formation and dentin mineralization. Researchers also will use it as a paradigm for patients with other diseases, such as periodontitis and aggressive periodontitis.

Hygiene Connection E-Newsletter

February 2015