{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T21:04:16Z","timestamp":1766869456938,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medicine at Otto von Guericke University Magdeburg"},{"name":"J\u00fcrgen Manchot Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The nuclear-encoded enzyme polymerase gamma (Pol-\u03b3) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-\u03b3, can significantly impair Pol-\u03b3 enzyme function. Pol-\u03b3-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C&gt;T; p.(Arg807Cys) and a previously undescribed variant c.678G&gt;C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-\u03b3 and mitochondrial dysfunction on the patient\u2019s fibroblasts, to test whether the novel variant c.678G&gt;C; p.(Gln226His) may be causative in human disease. Aims\/Methods: We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C&gt;T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology. Case Presentation and Results: A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G&gt;C; p.(Gln226His) and c.2419C&gt;T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C&gt;T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining. Conclusions: Our findings suggest that the c.678G&gt;C; p.(Gln226His) variant, in conjunction with the c.2419C&gt;T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G&gt;C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants.<\/jats:p>","DOI":"10.3390\/genes16020198","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T04:47:31Z","timestamp":1738817251000},"page":"198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The POLG Variant c.678G&gt;C; p.(Gln226His) Is Associated with Mitochondrial Abnormalities in Fibroblasts Derived from a Patient Compared to a First-Degree Relative"],"prefix":"10.3390","volume":"16","author":[{"given":"Imra","family":"Mantey","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Hospital Magdeburg, 39120 Magdeburg, Germany"},{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Langerscheidt","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c7a\u011fla","family":"\u00c7akmak Durmaz","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Baba","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, 07747 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Burghardt","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, 07747 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mert","family":"Karakaya","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7510-3077","authenticated-orcid":false,"given":"Hans","family":"Zempel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17802","DOI":"10.1074\/jbc.RA120.015390","article-title":"Polymerase \u03b3 Efficiently Replicates through Many Natural Template Barriers but Stalls at the HSP1 Quadruplex","volume":"295","author":"Sullivan","year":"2020","journal-title":"J. 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