Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Brain. 2017 Mar 1;140(3):568-581. doi: 10.1093/brain/awx002.

Ortal Barel ¹ ², May Christine V Malicdan ³ ⁴, Bruria Ben-Zeev ² ⁵ ⁶, Judith Kandel ⁷, Hadass Pri-Chen ³ ⁵, Joshi Stephen ³, Inês G Castro ⁸, Jeremy Metz ⁸, Osama Atawa ⁹, Sharon Moshkovitz ¹ ², Esther Ganelin ⁵ ⁶, Iris Barshack ⁵ ¹⁰, Sylvie Polak-Charcon ⁵ ¹⁰, Dvora Nass ⁵ ¹⁰, Dina Marek-Yagel ² ⁵ ¹¹, Ninette Amariglio ¹ ², Nechama Shalva ⁵ ¹¹, Thierry Vilboux ³ ¹², Carlos Ferreira ³ ¹³, Ben Pode-Shakked ⁵ ¹¹ ¹⁴, Gali Heimer ⁵ ⁶ ¹⁴, Chen Hoffmann ⁵ ¹⁵, Tal Yardeni ¹⁶, Andreea Nissenkorn ⁵ ¹⁷, Camila Avivi ¹⁰, Eran Eyal ¹ ², Nitzan Kol ¹ ², Efrat Glick Saar ¹ ², Douglas C Wallace ¹⁶, William A Gahl ³ ⁴, Gideon Rechavi ¹ ² ⁵, Michael Schrader ⁸, David M Eckmann ⁷ ¹⁸ ¹⁹, Yair Anikster ² ⁵ ¹¹

Affiliations

1 Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.
2 The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
3 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
4 NIH Undiagnosed Diseases Program, NHGRI, National Institutes of Health, Bethesda, Maryland, USA.
5 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
6 Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
7 Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
8 Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
9 Palestenian Red Crescent Society Hospital, Department of Pediatrics, Hebron City, Palestine.
10 Department of Pathology, Sheba Medical Center, Tel-Hashomer, Israel.
11 Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
12 Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
13 Division of Genetics and Metabolism, Children's National Health System, Washington DC, USA.
14 The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
15 Department of Radiology, Sheba Medical Center, Tel-Hashomer, Israel.
16 Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
17 Service for Rare Disorders, Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
18 Department of Anesthesiology and Critical Care, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
19 Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 28364549 DOI: 10.1093/brain/awx002

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.

Keywords

TRAK1; early-onset epilepsy; mitochondria transport; neurodegeneration; rare diseases.

Name
Email *

	Sorry, but the email address you supplied was invalid.