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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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.
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
© 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
DescriptionFunding: Royal Society grant RG110387 (S.P.)
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