SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency
| Autor: | Renzo Guerrini, Luna Laera, Sergio Giannattasio, Eleonora Paradies, Carlo M.T. Marobbio, Maria Anna Donati, Luigi Palmieri, Vito Porcelli, Eleonora Lamantea, Alessandra Castegna, Faruk Hossain, Alessio Menga, Anna De Grassi, Ciro Leonardo Pierri, Pasquale Scarcia, Francesco M. Lasorsa, Ruggiero Gorgoglione, Daniele Ghezzi, Isabella Pisano, Valeria Tiranti, Giuseppe Punzi, Matteo Ruggiu, Ferdinando Palmieri |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Mitochondrial DNA Heterozygote Mitochondrial Diseases Antioxidants Brain Diseases Child DNA Mitochondrial Dicarboxylic Acid Transporters Humans Metabolism Inborn Errors Mitochondria Mutation Oxidative Phosphorylation Oxidative Stress Pedigree RNA Splicing Mitochondrion Biology medicine.disease_cause 03 medical and health sciences Genetics medicine complex I deficiency Molecular Biology Gene Genetics (clinical) Exome sequencing encephalopathic epilepsy Inborn Errors RNA Heterozygote advantage General Medicine DNA Articles Mitochondrial carrier Mitochondrial 030104 developmental biology Metabolism exome sequencing slc25a10 |
| Zdroj: | Human molecular genetics 27 (2018): 499–504. doi:10.1093/hmg/ddx419 info:cnr-pdr/source/autori:Punzi, Giuseppe; Porcelli, Vito; Ruggiu, Matteo; Hossain, Md F; Menga, Alessio; Scarcia, Pasquale; Castegna, Alessandra; Gorgoglione, Ruggiero; Pierri, Ciro L; Laera, Luna; Lasorsa, Francesco M; Paradies, Eleonora; Pisano, Isabella; Marobbio, Carlo M T; Lamantea, Eleonora; Ghezzi, Daniele; Tiranti, Valeria; Giannattasio, Sergio; Donati, Maria A; Guerrini, Renzo; Palmieri, Luigi; Palmieri, Ferdinando; De Grassi, Anna/titolo:SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency./doi:10.1093%2Fhmg%2Fddx419/rivista:Human molecular genetics (Print)/anno:2018/pagina_da:499/pagina_a:504/intervallo_pagine:499–504/volume:27 |
| ISSN: | 1460-2083 |
| Popis: | Mitochondrial diseases are a plethora of inherited neuromuscular disorders sharing defects in mitochondrial respiration, but largely different from one another for genetic basis and pathogenic mechanism. Whole exome sequencing was performed in a familiar trio (trio-WES) with a child affected by severe epileptic encephalopathy associated with respiratory complex I deficiency and mitochondrial DNA depletion in skeletal muscle. By trio-WES we identified biallelic mutations in SLC25A10, a nuclear gene encoding a member of the mitochondrial carrier family. Genetic and functional analyses conducted on patient fibroblasts showed that SLC25A10 mutations are associated with reduction in RNA quantity and aberrant RNA splicing, and to absence of SLC25A10 protein and its transporting function. The yeast SLC25A10 ortholog knockout strain showed defects in mitochondrial respiration and mitochondrial DNA content, similarly to what observed in the patient skeletal muscle, and growth susceptibility to oxidative stress. Albeit patient fibroblasts were depleted in the main antioxidant molecules NADPH and glutathione, transport assays demonstrated that SLC25A10 is unable to transport glutathione. Here, we report the first recessive mutations of SLC25A10 associated to an inherited severe mitochondrial neurodegenerative disorder. We propose that SLC25A10 loss-of-function causes pathological disarrangements in respiratory-demanding conditions and oxidative stress vulnerability. |
| Databáze: | OpenAIRE |
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