Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Ortal Barel, May Christine V. Malicdan, Bruria Ben-Zeev, Judith Kandel, Hadass Pri-Chen, Joshi Stephen, Inês G. Castro, Jeremy Metz, Osama Atawa, Sharon Moshkovitz, Esther Ganelin, Iris Barshack, Sylvie Polak-Charcon, Dvora Nass, Dina Marek-Yagel, Ninette Amariglio, Nechama Shalva, Thierry Vilboux, Carlos Ferreira, Ben Pode-ShakkedGali Heimer, Chen Hoffmann, Tal Yardeni, Andreea Nissenkorn, Camila Avivi, Eran Eyal, Nitzan Kol, Efrat Glick Saar, Douglas C. Wallace, William A. Gahl, Gideon Rechavi, Michael Schrader, David M. Eckmann, Yair Anikster

Research output: Contribution to journalArticlepeer-review

Abstract

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A 4 C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.

Original languageEnglish
Pages (from-to)568-581
Number of pages14
JournalBrain
Volume140
Issue number3
DOIs
StatePublished - 1 Mar 2017

Keywords

  • Early-onset epilepsy
  • Mitochondria transport
  • Neurodegeneration
  • Rare diseases
  • TRAK1

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