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

Christopher Klein and colleagues report that DNMT1 is disrupted in hereditary sensory neuropathy with dementia and hearing loss. The mutations lead to reduced methyltransferase activity, leading to global hypomethylation and site-specific hypermethylation. DNA methyltransferase 1 (DNMT1) is crucial...

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Bibliographic Details
Published in:	Nature genetics Vol. 43; no. 6; pp. 595 - 600
Main Authors:	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, B Dyck, P James, Parisi, Joseph E, Mer, Georges, Smith, David I, Dyck, Peter J
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-06-2011 Nature Publishing Group
Subjects:	631/208/2489/144 631/208/737 692/699/375/365 Adolescent Adult Agriculture Amino acids Animal Genetics and Genomics Bacterial proteins Bioinformatics Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research Cell cycle Crystal structure Dementia Dementia - genetics Dementia disorders Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases - genetics DNA Methylation Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology Female Fundamental and applied biological sciences. Psychology G2 Phase Gene Function Gene mutations Genetic aspects Genetics of eukaryotes. Biological and molecular evolution Genomes Haplotypes Health aspects Hearing loss Hearing Loss - genetics Hereditary Sensory and Autonomic Neuropathies - genetics Heterochromatin - metabolism Human Genetics Humans letter Male Medical imaging Medical sciences Methyltransferases Middle Aged Models, Molecular Mortality Mutation Neurodegeneration Neuropathies, Hereditary motor and sensory Non tumoral diseases Otorhinolaryngology. Stomatology Physiological aspects Risk factors Science activities Tomography United States Nervous system diseases Auditory disorder ENT disease Degenerative disease Mutation Neuropathy Hereditary Dementia Hearing loss
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Summary:	Christopher Klein and colleagues report that DNMT1 is disrupted in hereditary sensory neuropathy with dementia and hearing loss. The mutations lead to reduced methyltransferase activity, leading to global hypomethylation and site-specific hypermethylation. DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability 1 , 2 , 3 . DNA mismatch repair, cell cycle regulation in post-mitotic neurons 4 , 5 and neurogenesis 6 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 7 , 8 . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors contributed equally
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng.830