TREX1 – TREX1-related Systemic Lupus Erythematosus

Three-prime repair exonuclease 1 (TREX1) is the major mammalian 3′→5′ DNA exonuclease responsible for clearing cytosolic DNA and preventing aberrant type I interferon (IFN) activation. Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by multi-organ inflammation and antinuclear antibodies. Genetic studies have implicated rare TREX1 variants in monogenic and complex forms of SLE, linking defective DNA degradation to IFN-mediated autoimmunity.

In a large multi-ancestral cohort, rare heterozygous TREX1 variants were identified in 9 of 417 unrelated SLE cases and absent in 1,712 controls (PMID:17660818). A landmark study in Nature Genetics reported monoallelic missense and frameshift mutations, including c.341G>A (p.Arg114His), with a significant case-control association (P=4.1×10⁻⁷). Moreover, whole-exome sequencing in a 4-year-old girl with early-onset cerebral lupus revealed a homozygous c.290G>A (p.Arg97His) variant, underscoring a recessive mechanism in severe pediatric presentations (PMID:25138095).

The spectrum of TREX1 mutations in SLE is dominated by missense changes within the nuclease domain. Recurrent variants include p.Arg114His and p.Arg240Ser, often occurring heterozygously but sometimes biallelically in early-onset cases. No robust pedigree segregation has been documented for adult-onset SLE, consistent with incomplete penetrance and multifactorial inheritance. Overall, the genetic architecture supports an autosomal dominant model for most SLE-associated alleles.

Functional assays demonstrate that p.Arg97His and p.Arg114His mutants reduce exonuclease activity by 20- to 35-fold and elevate type I IFN signatures in patient cells (PMID:25138095; PMID:18805785). In vivo, TREX1 D18N knock-in mice recapitulate systemic inflammation, vasculitis, renal immune complex deposition, and anti-dsDNA autoantibodies, mirroring human lupus pathology (PMID:25848017). These concordant experimental data provide a mechanistic link between TREX1 loss-of-function and SLE.

Collectively, genetic and functional data support a Strong gene–disease association for TREX1 and SLE, with Moderate genetic evidence and Strong functional evidence. While additional rare alleles and potential modifiers remain to be characterized, the existing body of work reaches the ClinGen genetic cap and demonstrates experimental concordance.

Key Take-home: Incorporation of TREX1 into SLE genetic testing panels, especially for early-onset or neuropsychiatric cases, can refine diagnosis and open avenues for targeted IFN-modulating therapies.

References

• Nature Genetics | 2007 | Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. PMID:17660818
• Arthritis & Rheumatology | 2014 | Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing. PMID:25138095
• 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 | 2015 | Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. PMID:25848017

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