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Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to include mild myopathy

Lookup NU author(s): Dr Kyle Thompson, Sila Hopton, Dr Langping He, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


AbstractObjective To determine the disease relevance of a novel de novo dominant variant in the SLC25A4 gene, encoding the muscle mitochondrial adenosine diphosphate (ADP)/adenosine triphosphate (ATP) carrier, identified in a child presenting with a previously unreported phenotype of mild childhood-onset myopathy.Methods Immunohistochemical and western blot analysis of the patient's muscle tissue were used to assay for the evidence of mitochondrial myopathy and for complex I–V protein levels. To determine the effect of a putative pathogenic p.Lys33Gln variant on ADP/ATP transport, the mutant protein was expressed in Lactococcus lactis and its transport activity was assessed with fused membrane vesicles.Results Our data demonstrate that the heterozygous c.97A>T (p.Lys33Gln) SLC25A4 variant is associated with classic muscle biopsy findings of mitochondrial myopathy (cytochrome c oxidase [COX]-deficient and ragged blue fibers), significantly impaired ADP/ATP transport in Lactococcus lactis and decreased complex I, III, and IV protein levels in patient's skeletal muscle. Nonetheless, the expression levels of the total ADP/ATP carrier (AAC) content in the muscle biopsy was largely unaffected.Conclusions This report further expands the clinical phenotype of de novo dominant SLC25A4 mutations to a childhood-onset, mild skeletal myopathy, without evidence of previously reported clinical features associated with SLC25A4-associated disease, such as cardiomyopathy, encephalopathy or ophthalmoplegia. The most likely reason for the milder disease phenotype is that the overall AAC expression levels were not affected, meaning that expression of the wild-type allele and other isoforms may in part have compensated for the impaired mutant variant.

Publication metadata

Author(s): King MS, Thompson K, Hopton S, He L, Kunji ERS, Taylor RW, Ortiz-Gonzalez XR

Publication type: Article

Publication status: Published

Journal: Neurology: Genetics

Year: 2018

Volume: 4

Issue: 4

Pages: 1-6

Print publication date: 01/08/2018

Online publication date: 20/07/2018

Acceptance date: 15/05/2018

Date deposited: 25/07/2018

ISSN (electronic): 2376-7839

Publisher: Wolters Kluwer Health


DOI: 10.1212/NXG.0000000000000256


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
Lily Foundation
MRC/EPSRC Molecular Pathology Node
UK NHS Highly Specialised Service of Rare Mitochondrial Disorders of Adults and Children
Robert Wood Johnson Foundation Harold Amos Faculty Development Award
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust