@article{e3fd0baeaf4541e589a354934510c584,
title = "Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss",
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.",
author = "Klein, {Christopher J.} and Botuyan, {Maria Victoria} and Yanhong Wu and Ward, {Christopher J.} and Nicholson, {Garth A.} and Simon Hammans and Kaori Hojo and Hiromitch Yamanishi and Karpf, {Adam R.} and Wallace, {Douglas C.} and Mariella Simon and Cecilie Lander and Boardman, {Lisa A.} and Cunningham, {Julie M.} and Smith, {Glenn E.} and Litchy, {William J.} and Benjamin Boes and Atkinson, {Elizabeth J.} and Sumit Middha and {B Dyck}, {P. James} and Parisi, {Joseph E.} and Georges Mer and Smith, {David I.} and Dyck, {Peter J.}",
note = "Funding Information: This study was supported by the National Institute of Neurologic Disorders and Strokes (NINDS) K08 (NS065007), NINDS R01 (NS36797) and a previous grant from the Muscular Dystrophy Association. The authors wish to thank the Mayo Center for Translational Science Activities (supported by NIH UL1 RR024150) and the Mayo Clinic Bioinformatics Core and Sequencing Core for their excellent assistance. We would also like to thank the support from the Clinical Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567). D.C.W. and M.S. would like to acknowledge the outstanding clinical contributions of J. Platt. Their portion of this work was supported by US National Institutes of Health grants NS21328 and NS070298.",
year = "2011",
month = jun,
doi = "10.1038/ng.830",
language = "English (US)",
volume = "43",
pages = "595--600",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "6",
}