TREX1 – Aicardi-Goutieres syndrome 1

Aicardi-Goutieres syndrome type 1 (AGS1) is an early-onset, interferon-mediated encephalopathy characterized by progressive neurodegeneration, intracranial calcifications, leukodystrophy, hepatosplenomegaly, elevated transaminases, thrombocytopenia, and systemic autoimmunity. AGS1 is caused by biallelic pathogenic variants in TREX1, the major mammalian 3′→5′ DNA exonuclease that prevents accumulation of immunostimulatory DNA in the cytosol (PMID:17357087).

Genetic evidence for AGS1 derives from multiple unrelated families harboring loss-of-function TREX1 alleles. In an Indian cohort, four unrelated probands with early-onset encephalopathy and lupus-like features were homozygous for a recurrent frameshift variant, c.223dup (p.Glu75GlyfsTer82), indicating a possible founder effect in this population (PMID:34303877). Across the literature, >50 affected individuals from >20 families carry biallelic TREX1 variants, including missense and truncating alleles, consistently presenting with AGS1.

TREX1-related AGS1 follows autosomal recessive inheritance, with pathogenic alleles including frameshift, nonsense, splice, and critical missense changes within the exonuclease domain. The recurrent c.223dup (p.Glu75GlyfsTer82) variant is a single-base duplication causing early truncation and loss of exonuclease function (PMID:34303877).

Functional studies demonstrate that TREX1 disease variants abrogate exonuclease activity and lead to accumulation of cytosolic DNA and type I interferon activation. Crystal structures of human and mouse TREX1 reveal that missense substitutions at catalytic residues (e.g., Arg114, Asp200) disrupt metal coordination and DNA binding, reducing enzymatic activity by 4–35,000-fold (PMID:17293595). The TREX1 D18N mutation causes dominant chilblain lupus, whereas the recessive R114H allele requires compound heterozygosity for AGS1, highlighting the importance of dimeric structure and heterozygous LoF mechanisms (PMID:18805785).

Animal models further support pathogenicity: mice engineered to express the TREX1 D18N allele develop lymphoid hyperplasia, vasculitis, kidney disease, and anti-dsDNA autoantibodies, recapitulating human lupus-like inflammation and underscoring the role of TREX1 in immune tolerance (PMID:25848017).

No conflicting evidence has been reported for biallelic TREX1 variants causing AGS1. The concordance of clinical, genetic, and functional data across independent cohorts establishes a definitive gene-disease relationship.

Key Take-home: Biallelic TREX1 loss-of-function variants cause autosomal recessive AGS1 via failure to degrade cytosolic DNA, leading to type I interferon–driven neuroinflammation and systemic autoimmunity. Genetic testing for TREX1 frameshift and missense alleles enables early, accurate diagnosis and informs potential interferon-targeted therapies.

References

• European journal of medical genetics • 2021 • Phenotypic variability of a TREX1 variant in Aicardi-Goutieres type 1 patients from the Indian subcontinent. PMID:34303877
• The Journal of biological chemistry • 2007 • The crystal structure of TREX1 explains the 3' nucleotide specificity and reveals a polyproline II helix for protein partnering. PMID:17293595
• The Journal of biological chemistry • 2008 • The TREX1 double-stranded DNA degradation activity is defective in dominant mutations associated with autoimmune disease. PMID:18805785
• 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
• American journal of human genetics • 2007 • Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. PMID:17357087

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