SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency

Giuseppe Punzi, Vito Porcelli, Matteo Ruggiu, Md F Hossain, Alessio Menga, Pasquale Scarcia, Alessandra Castegna, Ruggiero Gorgoglione, Ciro L Pierri, Luna Laera, Francesco M Lasorsa, Eleonora Paradies, Isabella Pisano, Carlo M T Marobbio, Eleonora Lamantea, Daniele Ghezzi, Valeria Tiranti, Sergio Giannattasio, Maria A Donati, Renzo GuerriniLuigi Palmieri, Ferdinando Palmieri, Anna De Grassi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)499-504
Number of pages6
JournalHuman Molecular Genetics
Volume27
Issue number3
DOIs
Publication statusPublished - Dec 1 2017

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Brain Diseases
Mitochondrial Diseases
Mitochondrial DNA
Mutation
Glutathione
Respiration
Skeletal Muscle
Oxidative Stress
Fibroblasts
Exome
RNA Splicing
Electron Transport Complex I
NADP
Neurodegenerative Diseases
Antioxidants
Yeasts
RNA
Growth
Genes
Proteins

Keywords

  • Journal Article

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Punzi, G., Porcelli, V., Ruggiu, M., Hossain, M. F., Menga, A., Scarcia, P., ... De Grassi, A. (2017). SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. Human Molecular Genetics, 27(3), 499-504. https://doi.org/10.1093/hmg/ddx419

SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. / 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.

In: Human Molecular Genetics, Vol. 27, No. 3, 01.12.2017, p. 499-504.

Research output: Contribution to journalArticle

Punzi, G, Porcelli, V, Ruggiu, M, Hossain, MF, Menga, A, Scarcia, P, Castegna, A, Gorgoglione, R, Pierri, CL, Laera, L, Lasorsa, FM, Paradies, E, Pisano, I, Marobbio, CMT, Lamantea, E, Ghezzi, D, Tiranti, V, Giannattasio, S, Donati, MA, Guerrini, R, Palmieri, L, Palmieri, F & De Grassi, A 2017, 'SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency', Human Molecular Genetics, vol. 27, no. 3, pp. 499-504. https://doi.org/10.1093/hmg/ddx419
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. / SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. In: Human Molecular Genetics. 2017 ; Vol. 27, No. 3. pp. 499-504.
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AU - Menga, Alessio

AU - Scarcia, Pasquale

AU - Castegna, Alessandra

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AU - Laera, Luna

AU - Lasorsa, Francesco M

AU - Paradies, Eleonora

AU - Pisano, Isabella

AU - Marobbio, Carlo M T

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AU - Ghezzi, Daniele

AU - Tiranti, Valeria

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AU - Donati, Maria A

AU - Guerrini, Renzo

AU - Palmieri, Luigi

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