000087630 001__ 87630
000087630 005__ 20210902121603.0
000087630 0247_ $$2doi$$a10.3389/fgene.2019.01300
000087630 0248_ $$2sideral$$a116071
000087630 037__ $$aART-2020-116071
000087630 041__ $$aeng
000087630 100__ $$0(orcid)0000-0001-5964-6138$$aEmperador, Sonia$$uUniversidad de Zaragoza
000087630 245__ $$aMolecular characterization of new FBXL4 mutations in patients with mtDNA depletion syndrome
000087630 260__ $$c2020
000087630 5060_ $$aAccess copy available to the general public$$fUnrestricted
000087630 5203_ $$aEncephalomyopathic 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.
000087630 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B33-17R$$9info:eu-repo/grantAgreement/ES/ISCIII/PI17-00021$$9info:eu-repo/grantAgreement/ES/ISCIII/PI17-00166$$9info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI17-00109
000087630 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000087630 590__ $$a4.599$$b2020
000087630 591__ $$aGENETICS & HEREDITY$$b48 / 175 = 0.274$$c2020$$dQ2$$eT1
000087630 592__ $$a1.413$$b2020
000087630 593__ $$aGenetics$$c2020$$dQ2
000087630 593__ $$aMolecular Medicine$$c2020$$dQ2
000087630 593__ $$aGenetics (clinical)$$c2020$$dQ2
000087630 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000087630 700__ $$0(orcid)0000-0003-0145-3020$$aGarrido-Pérez, Nuria$$uUniversidad de Zaragoza
000087630 700__ $$0(orcid)0000-0002-0432-0170$$aAmezcua-Gil, Javier$$uUniversidad de Zaragoza
000087630 700__ $$0(orcid)0000-0002-9779-8826$$aGaudó, Paula$$uUniversidad de Zaragoza
000087630 700__ $$aAndrés-Sanz, Julio Alberto
000087630 700__ $$aYubero, Delia
000087630 700__ $$aFernández-Marmiesse, Ana
000087630 700__ $$aO'Callaghan, Maria M
000087630 700__ $$aOrtigoza-Escobar, Juan D.
000087630 700__ $$aIriondo, Marti
000087630 700__ $$0(orcid)0000-0002-0269-7337$$aRuiz-Pesini, Eduardo$$uUniversidad de Zaragoza
000087630 700__ $$aGarcía-Cazorla, Angels
000087630 700__ $$aGil-Campos, Mercedes
000087630 700__ $$aArtuch, Rafael
000087630 700__ $$0(orcid)0000-0003-1770-6299$$aMontoya, Julio$$uUniversidad de Zaragoza
000087630 700__ $$0(orcid)0000-0002-8585-6371$$aBayona-Bafaluy, María Pilar$$uUniversidad de Zaragoza
000087630 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología
000087630 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000087630 773__ $$g10 (2020), 1300 1-10$$pFront. genet.$$tFrontiers in Genetics$$x1664-8021
000087630 8564_ $$s700789$$uhttps://zaguan.unizar.es/record/87630/files/texto_completo.pdf$$yVersión publicada
000087630 8564_ $$s97041$$uhttps://zaguan.unizar.es/record/87630/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000087630 909CO $$ooai:zaguan.unizar.es:87630$$particulos$$pdriver
000087630 951__ $$a2021-09-02-08:36:28
000087630 980__ $$aARTICLE