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Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo
OBJECTIVE: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC). METHODS: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Wolters Kluwer
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511247/ https://www.ncbi.nlm.nih.gov/pubmed/28748214 http://dx.doi.org/10.1212/NXG.0000000000000162 |
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author | McNeill, Nathan Nasca, Alessia Reyes, Aurelio Lemoine, Benjamin Cantarel, Brandi Vanderver, Adeline Schiffmann, Raphael Ghezzi, Daniele |
author_facet | McNeill, Nathan Nasca, Alessia Reyes, Aurelio Lemoine, Benjamin Cantarel, Brandi Vanderver, Adeline Schiffmann, Raphael Ghezzi, Daniele |
author_sort | McNeill, Nathan |
collection | PubMed |
description | OBJECTIVE: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC). METHODS: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity. RESULTS: Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an ∼11% decrease in the oxygen consumption rate and ∼43% decrease in the maximum respiratory rate in the patient's skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient's fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA (SNORD118) responsible for LCC. CONCLUSIONS: Here, we report seemingly pathogenic EARS2 mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant. CLINICALTRIALS.GOV IDENTIFIER: NCT00001671. |
format | Online Article Text |
id | pubmed-5511247 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Wolters Kluwer |
record_format | MEDLINE/PubMed |
spelling | pubmed-55112472017-07-26 Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo McNeill, Nathan Nasca, Alessia Reyes, Aurelio Lemoine, Benjamin Cantarel, Brandi Vanderver, Adeline Schiffmann, Raphael Ghezzi, Daniele Neurol Genet Article OBJECTIVE: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC). METHODS: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity. RESULTS: Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an ∼11% decrease in the oxygen consumption rate and ∼43% decrease in the maximum respiratory rate in the patient's skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient's fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA (SNORD118) responsible for LCC. CONCLUSIONS: Here, we report seemingly pathogenic EARS2 mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant. CLINICALTRIALS.GOV IDENTIFIER: NCT00001671. Wolters Kluwer 2017-07-14 /pmc/articles/PMC5511247/ /pubmed/28748214 http://dx.doi.org/10.1212/NXG.0000000000000162 Text en Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Article McNeill, Nathan Nasca, Alessia Reyes, Aurelio Lemoine, Benjamin Cantarel, Brandi Vanderver, Adeline Schiffmann, Raphael Ghezzi, Daniele Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title | Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title_full | Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title_fullStr | Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title_full_unstemmed | Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title_short | Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo |
title_sort | functionally pathogenic ears2 variants in vitro may not manifest a phenotype in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511247/ https://www.ncbi.nlm.nih.gov/pubmed/28748214 http://dx.doi.org/10.1212/NXG.0000000000000162 |
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