Cargando…
Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323106/ https://www.ncbi.nlm.nih.gov/pubmed/35885962 http://dx.doi.org/10.3390/genes13071179 |
_version_ | 1784756468823621632 |
---|---|
author | Amico, Giulia Hemphill, Wayne O. Severino, Mariasavina Moratti, Claudio Pascarella, Rosario Bertamino, Marta Napoli, Flavia Volpi, Stefano Rosamilia, Francesca Signa, Sara Perrino, Fred Zedde, Marialuisa Ceccherini, Isabella |
author_facet | Amico, Giulia Hemphill, Wayne O. Severino, Mariasavina Moratti, Claudio Pascarella, Rosario Bertamino, Marta Napoli, Flavia Volpi, Stefano Rosamilia, Francesca Signa, Sara Perrino, Fred Zedde, Marialuisa Ceccherini, Isabella |
author_sort | Amico, Giulia |
collection | PubMed |
description | 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. Our results for the p.A136V variant are inconsistent with prior biochemistry-pathology correlates for dominant AGS-causing TREX1 mutants. The p.R174G variant modestly altered exonuclease activity in a manner consistent 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. While the p.A136V variant is unlikely to be causative for AGS in Patient A, Patient B’s phenotype is potentially related to the p.R174G variant. Therefore, further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to determine any causal link and interrogate the molecular disease mechanism(s). |
format | Online Article Text |
id | pubmed-9323106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-93231062022-07-27 Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core Amico, Giulia Hemphill, Wayne O. Severino, Mariasavina Moratti, Claudio Pascarella, Rosario Bertamino, Marta Napoli, Flavia Volpi, Stefano Rosamilia, Francesca Signa, Sara Perrino, Fred Zedde, Marialuisa Ceccherini, Isabella Genes (Basel) Article 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. Our results for the p.A136V variant are inconsistent with prior biochemistry-pathology correlates for dominant AGS-causing TREX1 mutants. The p.R174G variant modestly altered exonuclease activity in a manner consistent 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. While the p.A136V variant is unlikely to be causative for AGS in Patient A, Patient B’s phenotype is potentially related to the p.R174G variant. Therefore, further functional investigations of TREX1 variants found in CADASIL-like patients are warranted to determine any causal link and interrogate the molecular disease mechanism(s). MDPI 2022-06-30 /pmc/articles/PMC9323106/ /pubmed/35885962 http://dx.doi.org/10.3390/genes13071179 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Amico, Giulia Hemphill, Wayne O. Severino, Mariasavina Moratti, Claudio Pascarella, Rosario Bertamino, Marta Napoli, Flavia Volpi, Stefano Rosamilia, Francesca Signa, Sara Perrino, Fred Zedde, Marialuisa Ceccherini, Isabella Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title | Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title_full | Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title_fullStr | Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title_full_unstemmed | Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title_short | Genotype-Phenotype Correlation and Functional Insights for Two Monoallelic TREX1 Missense Variants Affecting the Catalytic Core |
title_sort | genotype-phenotype correlation and functional insights for two monoallelic trex1 missense variants affecting the catalytic core |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323106/ https://www.ncbi.nlm.nih.gov/pubmed/35885962 http://dx.doi.org/10.3390/genes13071179 |
work_keys_str_mv | AT amicogiulia genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT hemphillwayneo genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT severinomariasavina genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT moratticlaudio genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT pascarellarosario genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT bertaminomarta genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT napoliflavia genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT volpistefano genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT rosamiliafrancesca genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT signasara genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT perrinofred genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT zeddemarialuisa genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT ceccheriniisabella genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore AT genotypephenotypecorrelationandfunctionalinsightsfortwomonoallelictrex1missensevariantsaffectingthecatalyticcore |