Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo
Citation Manager Formats
Make Comment
See Comments

Abstract
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.
GLOSSARY
- LCC=
- leukoencephalopathy, brain calcifications, and cysts;
- LTBL=
- leukoencephalopathy with thalamus and brainstem involvement and high lactate;
- MAF=
- minor allele frequency;
- MRR=
- maximum respiratory rate;
- OCR=
- oxygen consumption rate
Footnotes
↵* These authors contributed equally to this work.
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by the authors.
Supplemental data at Neurology.org/ng
- Received February 13, 2017.
- Accepted in final form April 18, 2017.
- 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), 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.
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Dr. Sevil Yaşar and Dr. Behnam Sabayan
► Watch
Topics Discussed
Alert Me
Recommended articles
-
Article
De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activitiesEwen W. Sommerville, Charlotte L. Alston, Angela Pyle et al.Neurology: Genetics, September 22, 2017 -
Article
Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunctionRichard G. Lee, Maryam Sedghi, Mehri Salari et al.Neurology: Genetics, October 05, 2018 -
Article
Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)Guido Zagnoli-Vieira, Francesco Bruni, Kyle Thompson et al.Neurology: Genetics, August 01, 2018 -
Article
Expanding the molecular and phenotypic spectrum of truncating MT-ATP6 mutationsEnrico Bugiardini, Emanuela Bottani, Silvia Marchet et al.Neurology: Genetics, January 08, 2020