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- Title
Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy.
- Authors
Barel, Ortal; Malicdan, May Christine V.; Ben-Zeev, Bruria; Kandel, Judith; Pri-Chen, Hadass; Stephen, Joshi; Castro, Inês G.; Metz, Jeremy; Atawa, Osama; Moshkovitz, Sharon; Ganelin, Eti; Barshack, Iris; Polak-Charcon, Sylvie; Nass, Dvora; Marek-Yagel, Dina; Amariglio, Ninette; Shalva, Nechama; Vilboux, Thierry; Ferreira, Carlos; Pode-Shakked, Ben
- 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 > 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.
- Subjects
MITOCHONDRIA; NEUROLOGICAL disorders; KINESIN; HUMAN genetic variation; NEURAL transmission; PROTEIN metabolism; BRAIN diseases; BIOLOGICAL transport; CELL culture; CONSANGUINITY; FAMILY health; FIBROBLASTS; GENETIC techniques; MAGNETIC resonance imaging; MEMBRANE proteins; PROTEINS; RESEARCH funding; OXYGEN consumption
- Publication
Brain: A Journal of Neurology, 2017, Vol 140, Issue 3, p568
- ISSN
0006-8950
- Publication type
journal article
- DOI
10.1093/brain/awx002