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A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism

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Date
07/08/2019
Author
Diquigiovanni, Chiara
Bergamini, Christian
Diaz, Rebeca
Liparulo, Irene
Bianco, Francesca
Masin, Luca
Baldassarro, Vito Antonio
Rizzardi, Nicola
Tranchina, Antonia
Bruscherini, Francesco
Wischmeijer, Anita
Pippucci, Tommaso
Scarano, Emanuela
Cordelli, Duccio Maria
Fato, Romana
Seri, Marco
Paracchini, Silvia
Bonora, Elena
Keywords
Spartin
Spg20
Mitochondria
QH301 Biology
QH426 Genetics
RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
NDAS
BDC
R2C
~DC~
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Abstract
Loss-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.
Citation
Diquigiovanni , 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 . https://doi.org/10.1096/fj.201802722R
Publication
FASEB Journal
Status
Peer reviewed
DOI
https://doi.org/10.1096/fj.201802722R
ISSN
0892-6638
Type
Journal article
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 https://doi.org/10.1096/fj.201802722R
Description
Funding: Royal Society grant RG110387 (S.P.)
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/18172

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