title: Homozygous nonsense mutation in SYNJ1 associated with intractable epilepsy and tau pathology.
abstract: The tauopathies are a heterogeneous group of neurodegenerative disorders characterized by the shared presence of tau aggregates and neurofibrillary tangles within the central nervous system. Here, we present a child with a severe neurodegenerative disorder characterized by intractable seizures and significant tau-immunoreactive neurofibrillary degeneration localized predominantly to the substantia nigra on neuropathology with absence of beta-amyloid plaques and Lewy or Pick bodies. Whole-exome sequencing identified a homozygous truncating mutation in Synaptojanin 1 (SYNJ1). Quantitative polymerase chain reaction and Western blot experiments demonstrated diminished SYNJ1 messenger RNA and protein. Knockout Synj1(-/-) mice have convulsions and die early in life. More recently, homozygous missense mutations have been reported in 2 families with early-onset parkinsonism and seizures. Our findings broaden the spectrum of disease associated with alteration of SYNJ1 and further implicate defects in synaptic vesicle recycling in the tauopathies.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: ddyment@cheo.on.ca.
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Smith
authors.affiliation: Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Humphreys
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Pathology and Laboratory Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Woulfe
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Michaud
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D000818:Animals; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*; D000099182:Phosphoinositide 5-Phosphatases
chemical_list: D018389:Codon, Nonsense; D010744:Phosphoric Monoester Hydrolases; D016875:tau Proteins; D000099182:Phosphoinositide 5-Phosphatases; C054369:MAPT protein, human
keywords: Seizures; Synaptojanin; Tauopathy; Whole-exome sequencing