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dc.contributor.authorDiquigiovanni, Chiara
dc.contributor.authorBergamini, Christian
dc.contributor.authorDiaz, Rebeca
dc.contributor.authorLiparulo, Irene
dc.contributor.authorBianco, Francesca
dc.contributor.authorMasin, Luca
dc.contributor.authorBaldassarro, Vito Antonio
dc.contributor.authorRizzardi, Nicola
dc.contributor.authorTranchina, Antonia
dc.contributor.authorBruscherini, Francesco
dc.contributor.authorWischmeijer, Anita
dc.contributor.authorPippucci, Tommaso
dc.contributor.authorScarano, Emanuela
dc.contributor.authorCordelli, Duccio Maria
dc.contributor.authorFato, Romana
dc.contributor.authorSeri, Marco
dc.contributor.authorParacchini, Silvia
dc.contributor.authorBonora, Elena
dc.identifier.citationDiquigiovanni , C , Bergamini , C , Diaz , R , Liparulo , I , Bianco , F , Masin , L , Baldassarro , V A , Rizzardi , N , Tranchina , A , Bruscherini , F , Wischmeijer , A , Pippucci , T , Scarano , E , Cordelli , D M , Fato , R , Seri , M , Paracchini , S & Bonora , E 2019 , ' A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism ' , FASEB Journal , vol. 33 , no. 10 , pp. 11284-11302 .
dc.identifier.otherPURE: 259408678
dc.identifier.otherPURE UUID: c217579a-db67-425e-bb61-80ad96a19505
dc.identifier.otherORCID: /0000-0003-0937-5928/work/60196513
dc.identifier.otherORCID: /0000-0001-9934-8602/work/60428068
dc.identifier.otherScopus: 85072717718
dc.identifier.otherWOS: 000489166300058
dc.descriptionFunding: Royal Society grant RG110387 (S.P.)en
dc.description.abstractLoss-of-function mutations in the SPART gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. SPART encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the SPART gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca2+ homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in SPART leads to a profound bioenergetic imbalance.
dc.relation.ispartofFASEB Journalen
dc.rights© 2019, FASEB. This work has been made available online in accordance with the publisher's policies. This is the author created submitted version manuscript before peer review and as such may differ from the final published version. The final published version of this work is available at
dc.subjectQH301 Biologyen
dc.subjectQH426 Geneticsen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.titleA novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolismen
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Centre for Biophotonicsen
dc.contributor.institutionUniversity of St Andrews.Cellular Medicine Divisionen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.description.statusPeer revieweden

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