UAB research probes molecular basis of rare genetic disorder

UAB research probes molecular basis of rare
genetic disorder

An international group of researchers has unraveled the molecular basis for the rare, inherited genetic disorder, Singleton-Merten Syndrome (SMS). Individuals with SMS develop extreme, life-threatening calcification of the aorta and heart valves, early-onset periodontitis, and root resorption of the teeth, decreases in bone density, and loss of bone tissue at the tips of fingers and toes.

The cause of SMS is a missense mutation that changes a single amino acid in the protein MDA5 from arginine to glutamine. That change in MDA5 — which detects viral double-stranded RNA as part of the innate immunity system — causes increased induction of interferon beta. Thus, SMS is recognized as an innate autoimmune disease for the first time. The findings are published in The American Journal of Human Genetics.

Functional studies by the UAB group found that:

• MDA5 — as measured by immunohistochemistry of human heart, skin, and cartilage tissue, or demineralized developing mouse teeth — was present in all target tissues that are altered in SMS.
• Presence of the SMS- IFIH1 mutant gene increased interferon beta gene expression by 20-fold, and correcting the single mutation of the SMS-IFIH1 back to normal reduced expression to control levels.
• The SMS- IFIH1 mutant gene had a greater response, as measured by interferon beta induction, when challenged with double-stranded RNA, as compared with the normal gene.
• Whole blood of SMS individuals and the cell lines developed from the SMS tooth had higher expression of interferon signature genes, compared with control individuals and cells.

The findings confirm that the altered gene is a gain-of-function mutation. Recently, IFIH1 has been linked to several autoimmune disorders, including Aicardi-Goutieres syndrome, though those individuals show brain and developmental defects.