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Singleton-Merten dysplasia is an autosomal-dominant innate immune disorder marked by dental and skeletal abnormalities, aortic calcification, psoriasis, and glaucoma. DDX58, encoding the viral RNA sensor RIG-I, harbors gain-of-function variants that drive type I interferon overproduction, underpinning both classic and atypical presentations of this syndrome.
Genetic studies have identified six distinct missense variants in at least 12 probands from five unrelated families, all showing autosomal-dominant inheritance and segregation of DDX58 variants with disease (PMID:25620203; 30574673; 33495304; 38752537). Variants localize to ATP-binding and helicase domains and include recurrent alleles in diverse populations, indicating mutational hotspots.
The variant spectrum comprises missense substitutions exclusively: c.803G>T (p.Cys268Phe), c.1118A>C (p.Glu373Ala), c.1529A>T (p.Glu510Val), and c.1649A>C (p.Asp550Ala). These changes perturb ATPase activity and RNA binding, leading to constitutive receptor activation and downstream signaling.
Functional assays in HEK293 and primary trabecular meshwork cells demonstrate that DDX58 mutants confer ligand-independent upregulation of type I IFN and interferon-stimulated genes, cytopathic effects, and reduced cell viability (PMID:25620203). In vivo, intraocular IFN-β injection in mice elevates intraocular pressure via autophagy activation—a process reversible by chloroquine—linking molecular dysfunction to hallmark glaucoma (PMID:38752537).
No studies have disputed the DDX58–Singleton-Merten association. Combined genetic and experimental data define a clear gain-of-function mechanism. While additional rare variants await characterization, current evidence supports robust diagnostic and therapeutic strategies for SMS.
Key Take-home: Gain-of-function DDX58 variants cause autosomal-dominant Singleton-Merten dysplasia by hyperactivating type I interferon signaling, enabling molecular diagnosis and targeted interventions.
Gene–Disease AssociationDefinitiveGain-of-function DDX58 variants in ≥5 unrelated families, cosegregation and functional validation (>12 affected individuals) Genetic EvidenceStrongSix distinct missense variants in 12 probands across five families; AD inheritance and segregation (PMID:25620203; 30574673; 33495304; 38752537) Functional EvidenceStrongConstitutive IFN activation in cellular assays, TM cell cytotoxicity, murine IOP model with rescue by autophagy inhibition (PMID:25620203; 38752537) |