Skip to content

Research at St Andrews

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

Research output: Contribution to journalArticle

Author(s)

Chiara Diquigiovanni, Christian Bergamini, Rebeca Diaz, Irene Liparulo, Francesca Bianco, Luca Masin, Vito Antonio Baldassarro, Nicola Rizzardi, Antonia Tranchina, Francesco Bruscherini, Anita Wischmeijer, Tommaso Pippucci, Emanuela Scarano, Duccio Maria Cordelli, Romana Fato, Marco Seri, Silvia Paracchini, Elena Bonora

School/Research organisations

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.
Close

Details

Original languageEnglish
Pages (from-to)11284-11302
Number of pages19
JournalFASEB Journal
Volume33
Issue number10
Early online date17 Jul 2019
DOIs
Publication statusPublished - 1 Oct 2019

    Research areas

  • Spartin, Spg20, Mitochondria

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Prevalence and heritability of handedness in a Chinese twin and singleton sample

    Zheng, M., McBride, C., Ho, C. S-H., Chan, J. K-C., Choy, K. W. & Paracchini, S., 22 Oct 2019, In : PsyArXiv. 31 p.

    Research output: Contribution to journalArticle

  2. Genomic imprinting as a window into human language evolution

    Hitchcock, T., Paracchini, S. & Gardner, A., Jun 2019, In : BioEssays. 41, 6, 11 p., 1800212.

    Research output: Contribution to journalArticle

Related by journal

  1. PLA2 and ENPP6 may act in concert to generate phosphocholine from the matrix vesicle membrane during skeletal mineralization

    Stewart, A. J., Leong, D. T. K. & Farquharson, C., Jan 2018, In : FASEB Journal. 32, 1, p. 20-25 6 p.

    Research output: Contribution to journalArticle

  2. Chronic exposure to imidacloprid increases neuronal vulnerability to mitochondrial dysfunction in the bumblebee (Bombus terrestris)

    Moffat, C., Goncalves Pacheco, J., Sharpe, S., Samson, A. J., Bollan, K. A., Huang, J., Buckland, S. T. & Connolly, C. N., May 2015, In : FASEB Journal. 29, 5, p. 2112-2119 8 p.

    Research output: Contribution to journalArticle

  3. Structure and mechanism of the CRISPR associated complex for antiviral defense (CASCADE)

    Lawrence, C. M., Lintner, N. G., Kerou, M. & White, M. F., Apr 2012, In : FASEB Journal. 26, 1 p.

    Research output: Contribution to journalAbstract

  4. D-Aspartic acid is a novel endogenous neurotransmitter

    D'Aniello, S., Somorjai, I. M. L., Garcia-Fernandez, J., Topo, E. & D'Aniello, A., Mar 2011, In : FASEB Journal. 25, 3, p. 1014-1027 14 p.

    Research output: Contribution to journalArticle

ID: 259408678

Top