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Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability(1-3). DNA mismatch repair, cell cycle regulation in post-mitotic neurons(4,5) and neurogenesis(6) are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central a...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102765/ https://www.ncbi.nlm.nih.gov/pubmed/21532572 http://dx.doi.org/10.1038/ng.830 |
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author | Klein, Christopher J. Botuyan, Maria-Victoria Wu, Yanhong Ward, Christopher J. Nicholson, Garth A. Hammans, Simon Hojo, Kaori Yamanishi, Hiromitch Karpf, Adam R. Wallace, Douglas C. Simon, Mariella Lander, Cecilie Boardman, Lisa A. Cunningham, Julie M. Smith, Glenn E. Litchy, William J. Boes, Benjamin Atkinson, Elizabeth J. Middha, Sumit Dyck, P. James Parisi, Joseph E. Mer, Georges Smith, David I. Dyck, Peter J. |
author_facet | Klein, Christopher J. Botuyan, Maria-Victoria Wu, Yanhong Ward, Christopher J. Nicholson, Garth A. Hammans, Simon Hojo, Kaori Yamanishi, Hiromitch Karpf, Adam R. Wallace, Douglas C. Simon, Mariella Lander, Cecilie Boardman, Lisa A. Cunningham, Julie M. Smith, Glenn E. Litchy, William J. Boes, Benjamin Atkinson, Elizabeth J. Middha, Sumit Dyck, P. James Parisi, Joseph E. Mer, Georges Smith, David I. Dyck, Peter J. |
author_sort | Klein, Christopher J. |
collection | PubMed |
description | DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability(1-3). DNA mismatch repair, cell cycle regulation in post-mitotic neurons(4,5) and neurogenesis(6) are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy (HSAN1) with dementia and hearing loss(7,8). Exome sequencing led to the identification of DNMT1 mutation c.A1484G (p.Tyr495Cys) in two American and one Japanese kindreds and a triple nucleotide change c.1470TCC-1472ATA (p.Asp490Glu-Pro491Tyr) in one European kindred. All mutations are within the targeting sequence (TS) 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 demonstrates DNMT1 mutations cause aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. |
format | Text |
id | pubmed-3102765 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-31027652011-12-01 Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss Klein, Christopher J. Botuyan, Maria-Victoria Wu, Yanhong Ward, Christopher J. Nicholson, Garth A. Hammans, Simon Hojo, Kaori Yamanishi, Hiromitch Karpf, Adam R. Wallace, Douglas C. Simon, Mariella Lander, Cecilie Boardman, Lisa A. Cunningham, Julie M. Smith, Glenn E. Litchy, William J. Boes, Benjamin Atkinson, Elizabeth J. Middha, Sumit Dyck, P. James Parisi, Joseph E. Mer, Georges Smith, David I. Dyck, Peter J. Nat Genet Article DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability(1-3). DNA mismatch repair, cell cycle regulation in post-mitotic neurons(4,5) and neurogenesis(6) are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy (HSAN1) with dementia and hearing loss(7,8). Exome sequencing led to the identification of DNMT1 mutation c.A1484G (p.Tyr495Cys) in two American and one Japanese kindreds and a triple nucleotide change c.1470TCC-1472ATA (p.Asp490Glu-Pro491Tyr) in one European kindred. All mutations are within the targeting sequence (TS) 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 demonstrates DNMT1 mutations cause aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases. 2011-05-01 2011-06 /pmc/articles/PMC3102765/ /pubmed/21532572 http://dx.doi.org/10.1038/ng.830 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Klein, Christopher J. Botuyan, Maria-Victoria Wu, Yanhong Ward, Christopher J. Nicholson, Garth A. Hammans, Simon Hojo, Kaori Yamanishi, Hiromitch Karpf, Adam R. Wallace, Douglas C. Simon, Mariella Lander, Cecilie Boardman, Lisa A. Cunningham, Julie M. Smith, Glenn E. Litchy, William J. Boes, Benjamin Atkinson, Elizabeth J. Middha, Sumit Dyck, P. James Parisi, Joseph E. Mer, Georges Smith, David I. Dyck, Peter J. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title | Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title_full | Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title_fullStr | Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title_full_unstemmed | Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title_short | Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss |
title_sort | mutations in dnmt1 cause hereditary sensory neuropathy with dementia and hearing loss |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102765/ https://www.ncbi.nlm.nih.gov/pubmed/21532572 http://dx.doi.org/10.1038/ng.830 |
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