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C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

Abstract

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3′-5′ exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

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Figure 1: Diagram of TREX1 protein.
Figure 2: Functional consequences of RVCL associated TREX1 mutations.

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Acknowledgements

We appreciate the cooperation of the participating families. We thank M. Bogacki, E. van den Boogerd, J. van Vark and S. Keradhmand-Kia. A.R. is a 2005/2006 Fulbright Distinguished Scholar. D.K. is a Kidney Research UK clinical training fellow. A.R. and D.K. are recipients of Peel Medical Trust Travel Fellowships. At Washington University in St. Louis, this study has been funded by the Center for Genome Sciences Pilot-Scale Sequencing Project Program and by the Danforth Foundation. The Netherlands Organization for Scientific Research (NWO) (Vici 918.56.602), the European Union “Eurohead” grant (LSHM-CT-2004-504837) and the Center of Medical System Biology established by the Netherlands Genomics Initiative/NWO supported the work in the Netherlands. US National Institutes of Health (NIH)/National Institute on Deafness and Other Communication Disorders (NIDCD) grant P50 DC02952 (R.W.B.), NIH/National Eye Institute grant R01 EY15311 and a Stein-Oppenheimer Award (J.C.J.) supported the work at University of California, Los Angeles. R.S. is the recipient of a scholarship from the German National Scholarship Foundation.

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Correspondence to John P Atkinson.

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Supplementary Text and Figures

Supplementary Methods, Supplementary Figure 1, Supplementary Tables 1–2 (PDF 476 kb)

Supplementary Video 1

Confocal microscopy video showing functional consequences of RVCL-associated TREX1 mutations as modeled in transiently expressed HEK293T cells. Fluorescent protein (green) and TOPRO3-stained nuclei (blue). Fluorescence expression pattern of fluorescent protein (FP) alone. The protein is diffusely distributed in the cytoplasm and in the nucleus. (MOV 121 kb)

Supplementary Video 2

Confocal microscopy video showing functional consequences of RVCL-associated TREX1 mutations as modeled in transiently expressed HEK293T cells. Fluorescent protein (green) and TOPRO3-stained nuclei (blue). Fluorescence expression pattern of wild-type TREX1 tagged with the fluorescent protein (FP-TREX1). This fusion protein is found in a perinuclear compartment and is excluded from the nucleus. (MOV 188 kb)

Supplementary Video 3

Confocal microscopy video showing functional consequences of RVCL-associated TREX1 mutations as modeled in transiently expressed HEK293T cells. Fluorescent protein (green) and TOPRO3 stained nuclei (blue). Fluorescence expression pattern of mutant TREX1, tagged with the fluorescent protein (FP-V235 fs). The mutant form of TREX1 exhibits an expression pattern identical to the fluorescent protein (FP) alone. (MOV 77 kb)

Supplementary Video 4

Confocal microscopy video showing functional consequences of RVCL-associated TREX1 mutations as modeled in transiently expressed HEK293T cells. Fluorescent protein (green) and TOPRO3-stained nuclei (blue). Fluorescence expression pattern of carboxyl-terminal 106 amino acids of TREX1 tagged with the fluorescent protein (FP-C-106). This fusion protein is found in a perinuclear compartment and is excluded from the nucleus. This pattern is identical to the native exonuclease, implicating this short stretch of amino acids in mediating the perinuclear localization of the protein. (MOV 191 kb)

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Richards, A., van den Maagdenberg, A., Jen, J. et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39, 1068–1070 (2007). https://doi.org/10.1038/ng2082

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