Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome
| Autor: | Sonia Emperador, Nuria Garrido-Pérez, Javier Amezcua-Gil, Paula Gaudó, Julio Alberto Andrés-Sanz, Delia Yubero, Ana Fernández-Marmiesse, Maria M. O’Callaghan, Juan D. Ortigoza-Escobar, Marti Iriondo, Eduardo Ruiz-Pesini, Angels García-Cazorla, Mercedes Gil-Campos, Rafael Artuch, Julio Montoya, María Pilar Bayona-Bafaluy |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mitochondrial DNA lcsh:QH426-470 Mitochondrial disease oxidative phosphorylation mitochondrial DNA Biology Frameshift mutation 03 medical and health sciences 0302 clinical medicine Genetics medicine Citrate synthase Missense mutation Genetics (clinical) Original Research FBXL4 mtDNA depletion mtDNA transcription Genetic disorder F-box leucine-rich repeat protein 4 medicine.disease Molecular biology Complementation mitochondrial disease lcsh:Genetics 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Molecular Medicine encephalomyopathic mtDNA depletion syndrome 13 |
| Zdroj: | Frontiers in Genetics, Vol 10 (2020) Zaguán. Repositorio Digital de la Universidad de Zaragoza instname Frontiers in Genetics |
| ISSN: | 1664-8021 |
| Popis: | Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation. |
| Databáze: | OpenAIRE |
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