A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome

Area of Science:

• Genetics
• Immunology
• Rare Diseases

Background:

• Singleton-Merten syndrome (SMS) is a rare autosomal-dominant disorder.
• SMS is characterized by severe aortic calcification, dental anomalies, osteopenia, and acro-osteolysis.

Purpose of the Study:

• To identify the molecular cause of Singleton-Merten syndrome.
• To investigate the role of the IFIH1 gene in SMS pathogenesis.

Main Methods:

• Whole-exome sequencing and Sanger sequencing were employed.
• Immunohistochemistry and in vitro functional assays were performed.
• Analysis of interferon signature genes in affected individuals.

Main Results:

• A recurrent missense mutation (c.2465G>A, p.Arg822Gln) in the IFIH1 gene (encoding MDA5) was identified in SMS patients.
• The mutation resulted in enhanced MDA5 function and increased interferon beta induction.
• Upregulation of interferon signature genes was observed in SMS individuals.

Conclusions:

• A gain-of-function mutation in IFIH1 is the molecular etiology of Singleton-Merten syndrome.
• The identified mutation leads to early arterial calcification and dental inflammation/resorption.
• This finding links IFIH1 to vascular and dental pathologies in SMS.