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Brain. 2015 Apr;138(Pt 4):845-61. doi: 10.1093/brain/awv010. Epub 2015 Feb 11.

Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.

Author information

1
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.
2
4 Peripheral Neuropathy Research Laboratory, Mayo Clinic, Rochester, MN, USA 5 Department of Neurology, China-Japan Friendship Hospital, Beijing China.
3
6 Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester MN, USA.
4
7 Department of Neurology, University of Utah, UT, USA.
5
8 Departments of Neurology and Pathology, University of California San Franciso, California, USA.
6
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.
7
9 Department of Medicine, Whangarei Hospital, Whangarei, New Zealand.
8
10 Department of Neurology, Oregon Health and Science University, Oregon, WA, USA.
9
11 Department of Biochemistry and Molecular Biology, Mayo Clinic Rochester MN, USA.
10
12 Epilepsy Research Laboratory, Department of Neurology, Mayo Clinic Rochester MN, USA.
11
13 Harima Sanatorium, Division of Neuropsychiatry, Hyogo, Japan.
12
14 Department of Neurology, University of California, San Francisco, California, USA.
13
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.
14
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.
15
19 Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University Munich, Munich, Germany.
16
20 Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
17
21 Centre de Référence Neuromusculaire, Cliniques universitaires St-Luc, Université de Louvain, Brussels, Belgium.
18
22 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
19
4 Peripheral Neuropathy Research Laboratory, Mayo Clinic, Rochester, MN, USA.
20
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.

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.

KEYWORDS:

REM sleep behaviour disorder; narcolepsy; neurodegeneration; protein aggregation; sensory neuropathy

PMID:
25678562
PMCID:
PMC5014076
DOI:
10.1093/brain/awv010
[Indexed for MEDLINE]
Free PMC Article

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