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Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy.


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.

SUBMITTER: Barel O 

PROVIDER: S-EPMC6075218 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy.

Barel Ortal O   Malicdan May Christine V MCV   Ben-Zeev Bruria B   Kandel Judith J   Pri-Chen Hadass H   Stephen Joshi J   Castro Inês G IG   Metz Jeremy J   Atawa Osama O   Moshkovitz Sharon S   Ganelin Esther E   Barshack Iris I   Polak-Charcon Sylvie S   Nass Dvora D   Marek-Yagel Dina D   Amariglio Ninette N   Shalva Nechama N   Vilboux Thierry T   Ferreira Carlos C   Pode-Shakked Ben B   Heimer Gali G   Hoffmann Chen C   Yardeni Tal T   Nissenkorn Andreea A   Avivi Camila C   Eyal Eran E   Kol Nitzan N   Glick Saar Efrat E   Wallace Douglas C DC   Gahl William A WA   Rechavi Gideon G   Schrader Michael M   Eckmann David M DM   Anikster Yair Y  

Brain : a journal of neurology 20170301 3


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 i  ...[more]

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