RT Journal Article
T1 Molecular Characterization of New FBXL4 Mutations in Patients With mtDNA Depletion Syndrome.
A1 Emperador, Sonia
A1 Garrido-Pérez, Nuria
A1 Amezcua-Gil, Javier
A1 Gaudó, Paula
A1 Andrés-Sanz, Julio Alberto
A1 Yubero, Delia
A1 Fernández-Marmiesse, Ana
A1 O'Callaghan, Maria M
A1 Ortigoza-Escobar, Juan D
A1 Iriondo, Marti
A1 Ruiz-Pesini, Eduardo
A1 García-Cazorla, Angels
A1 Gil-Campos, Mercedes
A1 Artuch, Rafael
A1 Montoya, Julio
A1 Bayona-Bafaluy, María Pilar
K1 F-box leucine-rich repeat protein 4
K1 encephalomyopathic mtDNA depletion syndrome 13
K1 mitochondrial DNA
K1 mitochondrial disease
K1 mtDNA depletion
K1 mtDNA transcription
K1 oxidative phosphorylation
AB 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.
SN 1664-8021
YR 2020
FD 2020-01-08
LK https://hdl.handle.net/10668/28286
UL https://hdl.handle.net/10668/28286
LA en
DS RISalud
RD Apr 17, 2025