Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic Trex1 Missense Variants Affecting the Catalytic Core

Version 1 : Received: 27 June 2022 / Approved: 28 June 2022 / Online: 28 June 2022 (04:08:17 CEST)

A peer-reviewed article of this Preprint also exists.

Amico, G.; Hemphill, W.O.; Severino, M.; Moratti, C.; Pascarella, R.; Bertamino, M.; Napoli, F.; Volpi, S.; Rosamilia, F.; Signa, S.; Perrino, F.; Zedde, M.; Ceccherini, I.; on behalf of the Gaslini Stroke Study Group. Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core. Genes 2022, 13, 1179. Amico, G.; Hemphill, W.O.; Severino, M.; Moratti, C.; Pascarella, R.; Bertamino, M.; Napoli, F.; Volpi, S.; Rosamilia, F.; Signa, S.; Perrino, F.; Zedde, M.; Ceccherini, I.; on behalf of the Gaslini Stroke Study Group. Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core. Genes 2022, 13, 1179.

Abstract

The TREX1 exonuclease degrades DNA to prevent aberrant nucleic acid sensing through the cGAS-STING pathway, and dominant Aicardi-Goutières Syndrome type 1 (AGS1) represents one of numerous TREX1-related autoimmune diseases. Monoallelic TREX1 mutations were identified in patients showing early-onset cerebrovascular disease, ascribable to small vessel disease, and CADASIL-like neuroimaging. We report the clinical-neuroradiological features of two patients with AGS-like (Patient A) and CADASIL-like (Patient B) phenotypes carrying the heterozygous p.A136V and p.R174G TREX1 variants, respectively. Genetic findings, obtained by a customized panel including 183 genes associated with monogenic stroke, were combined with interferon signature testing and biochemical assays to determine the mutations’ effects in vitro. Comprehensive studies revealed no pathological impact on TREX1 enzymatic function for the p.A136V variant. The p.R174G variant modestly altered exonuclease activity consistently with perturbation of substrate interaction rather than catalysis, which represents the first robust enzymological data for a TREX1 variant identified in a CADASIL-like patient. In conclusion, functional analysis allowed us to interpret the impact of TREX1 variants on patients’ phenotypes. Whilst Patient A’s manifestations are not related to p.A136V variant, Patient B’s phenotype is likely related to the p.R174G variant. Further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to establish a causal link and interrogate the molecular disease mechanism.

Keywords

exonuclease; autoimmunity; mutation; trex1

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

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