{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:50:48Z","timestamp":1786117848997,"version":"build-2736575974"},"reference-count":71,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019345","name":"King Salman Center for Disability Research","doi-asserted-by":"crossref","award":["2180 004, NK"],"award-info":[{"award-number":["2180 004, NK"]}],"id":[{"id":"10.13039\/501100019345","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2180 004, NK"],"award-info":[{"award-number":["2180 004, NK"]}],"id":[{"id":"https:\/\/ror.org\/01ht2b307","id-type":"ROR","asserted-by":"publisher"}]},{"name":"King Abdullah University of Science and Technology (KAUST)\u2014KAUST Center of Excellence for Smart Health","award":["5932"],"award-info":[{"award-number":["5932"]}]},{"award":["5932"],"award-info":[{"award-number":["5932"]}],"id":[{"id":"https:\/\/ror.org\/01q3tbs38","id-type":"ROR","asserted-by":"publisher"}]},{"name":"LifeArc Centre for Rare Mitochondrial Diseases","award":["10748"],"award-info":[{"award-number":["10748"]}]},{"DOI":"10.13039\/100011724","name":"MDUK","doi-asserted-by":"crossref","award":["23SI-PRG60-0013"],"award-info":[{"award-number":["23SI-PRG60-0013"]}],"id":[{"id":"10.13039\/100011724","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MR\/W019027\/1"],"award-info":[{"award-number":["MR\/W019027\/1"]}]},{"name":"UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust"},{"DOI":"10.13039\/501100022186","name":"Lily Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100022186","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G&gt;C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient\u2019s cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.<\/jats:p>","DOI":"10.3390\/ijms27156978","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:51:23Z","timestamp":1785772283000},"page":"6978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization"],"prefix":"10.3390","volume":"27","author":[{"given":"Mazhor","family":"Aldosary","sequence":"first","affiliation":[{"name":"Translational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"AlQudairy","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nourah","family":"Alshalan","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1050-3117","authenticated-orcid":false,"given":"Mohammad A.","family":"Al-Muhaizea","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"},{"name":"College of Medicine, Al Faisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Alobeid","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albandary","family":"AlBakheet","sequence":"additional","affiliation":[{"name":"Translational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 12713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-2821","authenticated-orcid":false,"given":"Ebtissal","family":"Khouj","sequence":"additional","affiliation":[{"name":"Personalized Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aljoharah M.","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa","family":"Alenazi","sequence":"additional","affiliation":[{"name":"Computational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanin R.","family":"Omar","sequence":"additional","affiliation":[{"name":"Computational Genomics Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi 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