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 > 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.
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Barel
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|NIH Undiagnosed Diseases Program, NHGRI, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: May Christine V
authors.initials: MCV
authors.lastname: Malicdan
authors.affiliation: The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Kandel
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Hadass
authors.initials: H
authors.lastname: Pri-Chen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
authors.forename: Inês G
authors.initials: IG
authors.lastname: Castro
authors.affiliation: Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Metz
authors.affiliation: Palestenian Red Crescent Society Hospital, Department of Pediatrics, Hebron City, Palestine.
authors.forename: Osama
authors.initials: O
authors.lastname: Atawa
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Moshkovitz
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Ganelin
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Pathology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Pathology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Polak-Charcon
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Pathology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Dvora
authors.initials: D
authors.lastname: Nass
authors.affiliation: The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Nechama
authors.initials: N
authors.lastname: Shalva
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Inova Translational Medicine Institute, Inova Health System, Falls Church, Virginia, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|Division of Genetics and Metabolism, Children's National Health System, Washington DC, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferreira
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Ben
authors.initials: B
authors.lastname: Pode-Shakked
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.|The Dr. Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Heimer
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Department of Radiology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Hoffmann
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Yardeni
authors.affiliation: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Service for Rare Disorders, Pediatric Neurology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Andreea
authors.initials: A
authors.lastname: Nissenkorn
authors.affiliation: Department of Pathology, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Eyal
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Kol
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Glick Saar
authors.affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.|NIH Undiagnosed Diseases Program, NHGRI, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Sheba Cancer Research Center, Sheba Medical Center, Tel-Hashomer, Israel.|The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.affiliation: Department of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Schrader
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Department of Anesthesiology and Critical Care, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.|Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Eckmann
authors.affiliation: The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel-Hashomer, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism*; D001927:Brain Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002478:Cells, Cultured; D002675:Child, Preschool; D003241:Consanguinity; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D056726:Genetic Association Studies; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000235:genetics*; D010101:Oxygen Consumption / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C531552:TRAK1 protein, human; D049452:Green Fluorescent Proteins
keywords: TRAK1; early-onset epilepsy; mitochondria transport; neurodegeneration; rare diseases