Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

Mayo Clinic, Department of Neurology, Division of Peripheral Nerve Diseases, Rochester, Minnesota, USA.
Nature Genetics (Impact Factor: 29.65). 06/2011; 43(6):595-600. DOI: 10.1038/ng.830
Source: PubMed

ABSTRACT DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability. DNA mismatch repair, cell cycle regulation in post-mitotic neurons and neurogenesis are influenced by DNA methylation. Here we show that mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy with dementia and hearing loss. Exome sequencing led to the identification of DNMT1 mutation c.1484A>G (p.Tyr495Cys) in two American kindreds and one Japanese kindred and a triple nucleotide change, c.1470-1472TCC>ATA (p.Asp490Glu-Pro491Tyr), in one European kindred. All mutations are within the targeting-sequence domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase leading to global hypomethylation and site-specific hypermethylation. Our study shows that DNMT1 mutations cause the aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.

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    • "Patient III-2 of Kindred 6 (C353F) is undergoing hemodialysis; the renal failure in Patient I-1 of Kindred 3 (Y524D) was attributed to amyloidosis due to chronic osteomyelitis, but this was not documented . A patient from the previously reported kindred (Klein et al., 2011) with Y495C also died of renal failure after chronic pyelonephritis; the kidneys showed an atrophied cortex and large numbers of nodules. At this point it remains unclear if the renal involvement is an accidental feature or in fact causally linked with DNMT1 mutations. "
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    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. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 02/2015; 138(4). DOI:10.1093/brain/awv010 · 10.23 Impact Factor
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    • "People with HSN1E develop hearing loss that is caused by abnormalities in the inner ear leading to sensorineural hearing loss (Wright and Dyck, 1995; Hojo et al., 1999; Klein et al., 2011). Hearing loss worsens over time and usually progresses to moderate or severe deafness between the ages of 20 and 35 (Wright and Dyck, 1995; Hojo et al., 1999; Klein et al., 2011). Mutations in DNMT1 typically cause bilateral hearing loss but unilateral hearing loss has also been reported (Melberg et al., 1995). "
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    ABSTRACT: The burgeoning field of epigenetics is beginning to make a significant impact on our understanding of tissue development, maintenance, and function. Epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues that direct cell-type specific gene networks. The inner ear is comprised of highly specialized cell types with identical genomes that originate from a single totipotent zygote. During inner ear development specific combinations of transcription factors and epigenetic modifiers must function in a coordinated manner to establish and maintain cellular identity. These epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns. In this review, we highlight emerging paradigms for epigenetic modifications related to inner ear development, and how epigenetics may have a significant role in hearing loss, protection, and regeneration.
    Frontiers in Cellular Neuroscience 01/2015; 8. DOI:10.3389/fncel.2014.00446 · 4.18 Impact Factor
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    • "Epigenetic modifications such as histone acetylation and DNA methylation play a paramount role in regulating gene expression and exhibit unique changes during aging and age-related disease (Fraga et al., 2007; Johnson et al., 2012). Modifications to epigenetic machinery can directly impact longevity (Lin et al., 2005) and health (Klein et al., 2011) as well as prevent differentiation of stem cells into somatic tissues "
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