Identification of a novel synaptic protein, TMTC3, involved in periventricular nodular heterotopia with intellectual disability and epilepsy.

Autor:	Farhan SMK; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7.; Department of Biochemistry., Nixon KCJ; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Everest M; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Edwards TN; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Long S; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Segal D; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Knip MJ; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Arts HH; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7.; Division of Genetics and Development, Children's Health Research Institute, London, ON, Canada, N6A 5W9.; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre Nijmegen, The Netherlands., Chakrabarti R; Division of Genetics and Development, Children's Health Research Institute, London, ON, Canada, N6A 5W9.; Department of Pediatrics., Wang J; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7., Robinson JF; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7., Lee D; Department of Medical Imaging., Mirsattari SM; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.; Departments of Clinical Neurological Sciences, Medical Biophysics, Medical Imaging and Psychology., Rupar CA; Department of Biochemistry.; Division of Genetics and Development, Children's Health Research Institute, London, ON, Canada, N6A 5W9.; Department of Pediatrics.; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Siu VM; Department of Biochemistry.; Division of Genetics and Development, Children's Health Research Institute, London, ON, Canada, N6A 5W9.; Department of Pediatrics., Poulter MO; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1., Hegele RA; Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada, N6A 5B7.; Department of Biochemistry., Kramer JM; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.; Division of Genetics and Development, Children's Health Research Institute, London, ON, Canada, N6A 5W9.; Department of Biology, Faculty of Science, Western University, London, ON, Canada, N6A 5B7.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2017 Nov 01; Vol. 26 (21), pp. 4278-4289.
DOI:	10.1093/hmg/ddx316
Abstrakt:	Defects in neuronal migration cause brain malformations, which are associated with intellectual disability (ID) and epilepsy. Using exome sequencing, we identified compound heterozygous variants (p.Arg71His and p. Leu729ThrfsTer6) in TMTC3, encoding transmembrane and tetratricopeptide repeat containing 3, in four siblings with nocturnal seizures and ID. Three of the four siblings have periventricular nodular heterotopia (PVNH), a common brain malformation caused by failure of neurons to migrate from the ventricular zone to the cortex. Expression analysis using patient-derived cells confirmed reduced TMTC3 transcript levels and loss of the TMTC3 protein compared to parental and control cells. As TMTC3 function is currently unexplored in the brain, we gathered support for a neurobiological role for TMTC3 by generating flies with post-mitotic neuron-specific knockdown of the highly conserved Drosophila melanogaster TMTC3 ortholog, CG4050/tmtc3. Neuron-specific knockdown of tmtc3 in flies resulted in increased susceptibility to induced seizures. Importantly, this phenotype was rescued by neuron-specific expression of human TMTC3, suggesting a role for TMTC3 in seizure biology. In addition, we observed co-localization of TMTC3 in the rat brain with vesicular GABA transporter (VGAT), a presynaptic marker for inhibitory synapses. TMTC3 is localized at VGAT positive pre-synaptic terminals and boutons in the rat hypothalamus and piriform cortex, suggesting a role for TMTC3 in the regulation of GABAergic inhibitory synapses. TMTC3 did not co-localize with Vglut2, a presynaptic marker for excitatory neurons. Our data identified TMTC3 as a synaptic protein that is involved in PVNH with ID and epilepsy, in addition to its previously described association with cobblestone lissencephaly. (© The Author 2017. Published by Oxford University Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu