title: Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.
abstract: We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.
authors: 1 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium 3 Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.
authors: Jonathan
authors: J
authors: Baets
authors: 4 Peripheral Neuropathy Research Laboratory, Mayo Clinic, Rochester, MN, USA 5 Department of Neurology, China-Japan Friendship Hospital, Beijing China.
authors: Xiaohui
authors: X
authors: Duan
authors: 6 Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester MN, USA.
authors: Yanhong
authors: Y
authors: Wu
authors: 7 Department of Neurology, University of Utah, UT, USA.
authors: Gordon
authors: G
authors: Smith
authors: 8 Departments of Neurology and Pathology, University of California San Franciso, California, USA.
authors: William W
authors: WW
authors: Seeley
authors: 1 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.
authors: Inès
authors: I
authors: Mademan
authors: 9 Department of Medicine, Whangarei Hospital, Whangarei, New Zealand.
authors: Nicole M
authors: NM
authors: McGrath
authors: 10 Department of Neurology, Oregon Health and Science University, Oregon, WA, USA.
authors: Noah C
authors: NC
authors: Beadell
authors: 10 Department of Neurology, Oregon Health and Science University, Oregon, WA, USA.
authors: Julie
authors: J
authors: Khoury
authors: 11 Department of Biochemistry and Molecular Biology, Mayo Clinic Rochester MN, USA.
authors: Maria-Victoria
authors: MV
authors: Botuyan
authors: 11 Department of Biochemistry and Molecular Biology, Mayo Clinic Rochester MN, USA.
authors: Georges
authors: G
authors: Mer
authors: 12 Epilepsy Research Laboratory, Department of Neurology, Mayo Clinic Rochester MN, USA.
authors: Gregory A
authors: GA
authors: Worrell
authors: 13 Harima Sanatorium, Division of Neuropsychiatry, Hyogo, Japan.
authors: Kaori
authors: K
authors: Hojo
authors: 14 Department of Neurology, University of California, San Francisco, California, USA.
authors: Jessica
authors: J
authors: DeLeon
authors: 15 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK 16 Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors: Matilde
authors: M
authors: Laura
authors: 15 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK 16 Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK 17 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 18 National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Yo-Tsen
authors: YT
authors: Liu
authors: 19 Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University Munich, Munich, Germany.
authors: Jan
authors: J
authors: Senderek
authors: 20 Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
authors: Joachim
authors: J
authors: Weis
authors: 21 Centre de Référence Neuromusculaire, Cliniques universitaires St-Luc, Université de Louvain, Brussels, Belgium.
authors: Peter
authors: P
authors: Van den Bergh
authors: 22 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Shana L
authors: SL
authors: Merrill
authors: 15 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK 16 Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors: Mary M
authors: MM
authors: Reilly
authors: 15 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK 16 Department of Molecular Neuroscience, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors: Henry
authors: H
authors: Houlden
authors: 22 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Murray
authors: M
authors: Grossman
authors: 22 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors: Steven S
authors: SS
authors: Scherer
authors: 1 Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium 2 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium 3 Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium.
authors: Peter
authors: P
authors: De Jonghe
authors: 4 Peripheral Neuropathy Research Laboratory, Mayo Clinic, Rochester, MN, USA.
authors: Peter J
authors: PJ
authors: Dyck
authors: 4 Peripheral Neuropathy Research Laboratory, Mayo Clinic, Rochester, MN, USA 6 Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester MN, USA 23 Department of Medical Genetics, Mayo Clinic Rochester MN, USA klein.christopher@mayo.edu.
authors: Christopher J
authors: CJ
authors: Klein
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009422:Nervous System Diseases / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D017433:Protein Structure, Secondary
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
keywords: REM sleep behaviour disorder; narcolepsy; neurodegeneration; protein aggregation; sensory neuropathy