New roles for the major human 3'-5' exonuclease TREX1 in human disease

Abstract

Aicardi-Goutières syndrome (AGS), Systemic Lupus Erythematosus (SLE), Familial Chilblain Lupus (FCL) and Retinal Vasculopathy and Cerebral Leukodystrophy (RVCL) {a new term encompassing three independently described conditions with a common etiology--Cerebroretinal Vasculopathy (CRV), Hereditary Vascular Retinopathy (HVR) and Hereditary Endotheliopathy, Retinopathy and Nephropathy (HERNS)}--have previously been regarded as distinct entities. However, recent genetic analysis has demonstrated that each of these diseases maps to chromosome 3p21 and can be caused by mutations in TREX1, the major human 3'-5' exonuclease. In this review, we discuss the putative functions of TREX1 in relationship to the clinical, genetic and functional characteristics of each of these conditions.

Figure 1

Schematic diagram of the TREX1 protein structure with sites of mutations associated with human disease. Numbers for each mutation correspond with those listed in Table 1. Regions I, II and III represent the exonuclease domains (Exo I–III). Region P represents the polyproline II helix (PPII). Region TMD represents the putative transmembrane domain.

Figure 2

Functional consequences of TREX1 mutations associated with RVCL. Confocal microscopy of HEK293T cells showing transiently expressed yellow fluorescent protein (eYFP)-tagged TREX1 proteins (green), TOPRO3 staining of nuclei (red), and the overlay for eYFP alone (A), wild-type TREX1 (B), and the CRV mutant form of TREX1 (C) as well as the corresponding intensity profile for each across region of drawn arrow (D).