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.