Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutières syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1.
The TREX1 proteins containing R114H and the insertion mutations aspartate at position 201 (D201ins) and alanine at position 124 (A124ins), found in compound heterozygous AGS with R114H, were prepared and the DNA degradation activities were tested.
Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.
A TREX1-mutated lymphocyte cell line was derived from an Aicardi-Goutières syndrome patient and co-cultured with neuroblastoma cells and vascular endothelial cells in the presence of interferon α. TREX1-mutated lymphocytes exerted marked inhibitory action on neuroblastoma cell growth.
Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.
Trex1 is the major 3' DNA exonuclease in mammalian cells, and mutations in the human TREX1 gene can cause Aicardi-Goutières syndrome, characterized by perturbed immunity.
Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus-like disease Aicardi-Goutières syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP-AMP synthase-dependent type I IFN response and systemic autoimmunity.
This study is the first to report a nationwide AGS survey, which identified more patients with sporadic AGS carrying de novo dominant-type TREX1 mutations than expected.
Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5.
Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity.
They found that TREX1-deficiency resulted in the intracellular accumulation of single stranded DNA resulting in chronic activation of the DNA damage response network, even in cells from Trex1-mutated AGS patients.
Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS).