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-Shakked; Gali 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

doi:10.1093/brain/awx002

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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 language	English
Pages (from-to)	568-581
Number of pages	14
Journal	Brain
Volume	140
Issue number	3
DOIs	https://doi.org/10.1093/brain/awx002
State	Published - 1 Mar 2017

Funding

Funders	Funder number
Israeli Centers of Excellence
NGHRI
Kahn Family Foundation
Wellcome Trust	316723, WT105618MA, WT097835MF
Israeli Centers for Research Excellence
UK Research and Innovation
NIH Office of the Director	R01OD010944
Office of Naval Research	N000141410538
Israel Science Foundation	41/11
Biotechnology and Biological Sciences Research Council	BB/K006231/1
National Human Genome Research Institute	ZIDHG200352, ZIAHG000215

Keywords

Early-onset epilepsy
Mitochondria transport
Neurodegeneration
Rare diseases
TRAK1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/brain/awx002

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Barel, O., Malicdan, M. C. V., Ben-Zeev, B., Kandel, J., Pri-Chen, H., Stephen, J., Castro, I. G., Metz, J., Atawa, O., Moshkovitz, S., Ganelin, E., Barshack, I., Polak-Charcon, S., Nass, D., Marek-Yagel, D., Amariglio, N., Shalva, N., Vilboux, T., Ferreira, C., ... Anikster, Y. (2017). Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy. Brain, 140(3), 568-581. https://doi.org/10.1093/brain/awx002

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title = "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 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.",

keywords = "Early-onset epilepsy, Mitochondria transport, Neurodegeneration, Rare diseases, TRAK1",

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

note = "Publisher Copyright: {\textcopyright} Published by Oxford University Press on behalf of the Guarantors of Brain 2017.",

year = "2017",

month = mar,

day = "1",

doi = "10.1093/brain/awx002",

language = "אנגלית",

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journal = "Brain",

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Barel, O, Malicdan, MCV, Ben-Zeev, B, Kandel, J, Pri-Chen, H, Stephen, J, Castro, IG, Metz, J, Atawa, O, Moshkovitz, S, Ganelin, E, Barshack, I, Polak-Charcon, S, Nass, D, Marek-Yagel, D, Amariglio, N, Shalva, N, Vilboux, T, Ferreira, C, Pode-Shakked, B , Heimer, G , Hoffmann, C, Yardeni, T, Nissenkorn, A, Avivi, C, Eyal, E, Kol, N, Saar, EG, Wallace, DC, Gahl, WA, Rechavi, G, Schrader, M, Eckmann, DM & Anikster, Y 2017, 'Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy', Brain, vol. 140, no. 3, pp. 568-581. https://doi.org/10.1093/brain/awx002

TY - JOUR

T1 - Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

AU - Barel, Ortal

AU - Malicdan, May Christine V.

AU - Ben-Zeev, Bruria

AU - Kandel, Judith

AU - Pri-Chen, Hadass

AU - Stephen, Joshi

AU - Castro, Inês G.

AU - Metz, Jeremy

AU - Atawa, Osama

AU - Moshkovitz, Sharon

AU - Ganelin, Esther

AU - Barshack, Iris

AU - Polak-Charcon, Sylvie

AU - Nass, Dvora

AU - Marek-Yagel, Dina

AU - Amariglio, Ninette

AU - Shalva, Nechama

AU - Vilboux, Thierry

AU - Ferreira, Carlos

AU - Pode-Shakked, Ben

AU - Heimer, Gali

AU - Hoffmann, Chen

AU - Yardeni, Tal

AU - Nissenkorn, Andreea

AU - Avivi, Camila

AU - Eyal, Eran

AU - Kol, Nitzan

AU - Saar, Efrat Glick

AU - Wallace, Douglas C.

AU - Gahl, William A.

AU - Rechavi, Gideon

AU - Schrader, Michael

AU - Eckmann, David M.

AU - Anikster, Yair

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - Early-onset epilepsy

KW - Mitochondria transport

KW - Neurodegeneration

KW - Rare diseases

KW - TRAK1

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DO - 10.1093/brain/awx002

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AN - SCOPUS:85028518310

SN - 0006-8950

VL - 140

SP - 568

EP - 581

JO - Brain

JF - Brain

IS - 3

ER -

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Abstract

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Keywords

UN SDGs

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