TREX1 – Aicardi-Goutières syndrome

Aicardi-Goutières syndrome (AGS) is a genetically determined early-onset encephalopathy that mimics congenital viral infection. Biallelic loss-of-function variants in TREX1 account for the AGS1 subtype, with mutations detected in approximately 25% of patients ([PMID:17846997]). Rare de novo heterozygous TREX1 mutations can also produce an autosomal dominant AGS phenotype, often with additional mitochondrial dysfunction features ([PMID:20799324]).

Inheritance of AGS1 is primarily autosomal recessive, with biallelic null or missense changes in TREX1 leading to type I interferonopathy. Segregation analysis identified pathogenic variants in 31 unrelated families, confirming co-segregation of disease within pedigrees ([PMID:17846997]). Two independent de novo heterozygous variants expand the inheritance spectrum to include dominant-negative effects ([PMID:17357087]; [PMID:20799324]).

The TREX1 variant spectrum in AGS includes missense substitutions (e.g., c.52G>A (p.Asp18Asn)), frameshifts, splice-site, and deep-intronic changes. The recurrent c.223dup (p.Glu75GlyfsTer82) variant shows a possible founder effect in Indian patients ([PMID:34303877]). Functional prediction and population data support pathogenicity of these alleles.

Functional studies demonstrate that disease-associated TREX1 mutants profoundly impair 3′→5′ exonuclease activity, leading to accumulation of immunostimulatory nucleic acids. Crystal structures reveal disrupted active-site metal coordination and DNA binding in D18N and D200N variants ([PMID:17293595]; [PMID:22071149]). A TREX1 D18N knock-in mouse model develops lupus-like autoimmunity with vasculitis and kidney disease, mirroring human AGS clinical features ([PMID:25848017]).

Clinical phenotypes include neonatal encephalopathy, intracranial calcifications, leukodystrophy, spasticity, seizures, and hepatosplenomegaly. Variable autoimmune manifestations, such as chilblain lupus or thyroiditis, overlap with systemic lupus erythematosus in some patients ([PMID:23918923]; [PMID:35551623]).

Integration of genetic and experimental data establishes a definitive TREX1–AGS association. Diagnostic testing for TREX1 variants should be prioritized in early-onset interferonopathy, guiding management and genetic counseling. Key Take-home: Pathogenic TREX1 variants cause a definitive AGS1 phenotype via loss of exonuclease function and aberrant type I interferon signaling, supporting targeted genetic and therapeutic strategies.

References

• American journal of human genetics • 2007 • Clinical and molecular phenotype of Aicardi-Goutieres syndrome PMID:17846997
• American journal of medical genetics. Part A • 2010 • A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres syndrome PMID:20799324
• American journal of human genetics • 2007 • Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome PMID:17357087
• Proceedings of the National Academy of Sciences of the United States of America • 2015 • Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease PMID:25848017
• World journal of pediatrics : WJP • 2022 • Analysis of clinical characteristics of children with Aicardi-Goutieres syndrome in China PMID:35551623

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