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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 stability1,2,3. DNA mismatch repair, cell cycle regulation in post-mitotic neurons4,5 and neurogenesis6 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 loss7,8. 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.

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Figure 1: Pathology of an individual with HSAN1 with dementia and hearing loss.
Figure 2: DNMT1 mutations in studied HSAN1 kindreds with dementia and hearing loss.
Figure 3: Localization of the wild-type and mutant targeting sequence domain of DNMT1.
Figure 4: Heterochromatin and replication foci binding of wild-type and mutant DNMT1.
Figure 5: Methylation profile difference between the affected and the unaffected groups.

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NCBI Reference Sequence

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  1. Feng, J. & Fan, G. The role of DNA methylation in the central nervous system and neuropsychiatric disorders. Int. Rev. Neurobiol. 89, 67–84 (2009).

    Article  CAS  Google Scholar 

  2. Chen, W.G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).

    Article  CAS  Google Scholar 

  3. Tohgi, H. et al. Reduction with age in methylcytosine in the promoter region –224 approximately –101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res. Mol. Brain Res. 70, 288–292 (1999).

    Article  CAS  Google Scholar 

  4. Herrup, K. & Yang, Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat. Rev. Neurosci. 8, 368–378 (2007).

    Article  CAS  Google Scholar 

  5. Brooks, P.J., Marietta, C. & Goldman, D. DNA mismatch repair and DNA methylation in adult brain neurons. J. Neurosci. 16, 939–945 (1996).

    Article  CAS  Google Scholar 

  6. Fan, G. et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21, 788–797 (2001).

    Article  CAS  Google Scholar 

  7. Wright, A. & Dyck, P.J. Hereditary sensory neuropathy with sensorineural deafness and early-onset dementia. Neurology 45, 560–562 (1995).

    Article  CAS  Google Scholar 

  8. Hojo, K. et al. Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study. Eur. J. Neurol. 6, 357–361 (1999).

    Article  CAS  Google Scholar 

  9. Klein, C.J. & Dyck, P. Hereditary sensory and autonomic neuropathies (HSAN): clinical features pathologic classification, and molecular genetics. in Peripheral Neuropathy, Fourth Edition, Vol. 2 (eds. Peter J. Dyck & P.K. Thomas) 1809–1845 (Philadelphia, USA, 2005).

  10. Dawkins, J.L., Hulme, D.J., Brahmbhatt, S.B., Auer-Grumbach, M. & Nicholson, G.A. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat. Genet. 27, 309–312 (2001).

    Article  CAS  Google Scholar 

  11. Rotthier, A. et al. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am. J. Hum. Genet. 87, 513–522 (2010).

    Article  CAS  Google Scholar 

  12. Guelly, C. et al. Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am. J. Hum. Genet. 88, 99–105 (2011).

    Article  CAS  Google Scholar 

  13. Verhoeven, K. et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am. J. Hum. Genet. 72, 722–727 (2003).

    Article  CAS  Google Scholar 

  14. Hojo, K., Kawamata, T., Tanaka, C. & Maeda, K. Inflammatory glial activation in the brain of a patient with hereditary sensory neuropathy type 1 with deafness and dementia. Neurosci. Lett. 367, 340–343 (2004).

    Article  CAS  Google Scholar 

  15. Fatemi, M., Hermann, A., Pradhan, S. & Jeltsch, A. The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J. Mol. Biol. 309, 1189–1199 (2001).

    Article  CAS  Google Scholar 

  16. Margot, J.B. et al. Structure and function of the mouse DNA methyltransferase gene: Dnmt1 shows a tripartite structure. J. Mol. Biol. 297, 293–300 (2000).

    Article  CAS  Google Scholar 

  17. Leonhardt, H., Page, A.W., Weier, H.U. & Bestor, T.H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865–873 (1992).

    Article  CAS  Google Scholar 

  18. Fellinger, K., Rothbauer, U., Felle, M., Langst, G. & Leonhardt, H. Dimerization of DNA methyltransferase 1 is mediated by its regulatory domain. J. Cell. Biochem. 106, 521–528 (2009).

    Article  CAS  Google Scholar 

  19. Cardoso, M.C. & Leonhardt, H. DNA methyltransferase is actively retained in the cytoplasm during early development. J. Cell Biol. 147, 25–32 (1999).

    Article  CAS  Google Scholar 

  20. Easwaran, H.P., Schermelleh, L., Leonhardt, H. & Cardoso, M.C. Replication-independent chromatin loading of Dnmt1 during G2 and M phases. EMBO Rep. 5, 1181–1186 (2004).

    Article  CAS  Google Scholar 

  21. Spada, F. et al. DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J. Cell Biol. 176, 565–571 (2007).

    Article  CAS  Google Scholar 

  22. Song, L., James, S.R., Kazim, L. & Karpf, A.R. Specific method for the determination of genomic DNA methylation by liquid chromatography-electrospray ionization tandem mass spectrometry. Anal. Chem. 77, 504–510 (2005).

    Article  CAS  Google Scholar 

  23. Chen, T. et al. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Nat. Genet. 39, 391–396 (2007).

    Article  CAS  Google Scholar 

  24. Brown, K.D. & Robertson, K.D. DNMT1 knockout delivers a strong blow to genome stability and cell viability. Nat. Genet. 39, 289–290 (2007).

    Article  CAS  Google Scholar 

  25. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).

    Article  CAS  Google Scholar 

  26. Jones, P.A. & Baylin, S.B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).

    Article  CAS  Google Scholar 

  27. Nelson, E.D., Kavalali, E.T. & Monteggia, L.M. Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J. Neurosci. 28, 395–406 (2008).

    Article  CAS  Google Scholar 

  28. Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).

    Article  CAS  Google Scholar 

  29. Xu, G.L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    Article  CAS  Google Scholar 

  30. Cao, X. & Sudhof, T.C. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115–120 (2001).

    Article  CAS  Google Scholar 

  31. Wijsman, E.M. et al. Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2. Am. J. Hum. Genet. 75, 398–409 (2004).

    Article  CAS  Google Scholar 

  32. Tawa, R., Ono, T., Kurishita, A., Okada, S. & Hirose, S. Changes of DNA methylation level during pre- and postnatal periods in mice. Differentiation 45, 44–48 (1990).

    Article  CAS  Google Scholar 

  33. Spada, F., Rothbauer, U., Zolghadr, K., Schermelleh, L. & Leonhardt, H. Regulation of DNA methyltransferase 1. Adv. Enzyme Regul. 46, 224–234 (2006).

    Article  CAS  Google Scholar 

  34. Golshani, P., Hutnick, L., Schweizer, F. & Fan, G. Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation. Thalamus Relat. Syst. 3, 227–233 (2005).

    Article  CAS  Google Scholar 

  35. Rampon, C. et al. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat. Neurosci. 3, 238–244 (2000).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations



C.J.K., D.I.S. and P.J.D. directed the study. C.J.K. wrote the paper. C.J.K., P.J.B.D., G.A.N., S.H., K.H., H.Y., D.C.W., M.S., C.L., L.A.B., G.E.S. and W.J.L. evaluated or collated subject data. E.J.A. did the linkage and haplotype analysis. S.M. and B.B. did the next generation sequencing analysis. C.J.K., C.J.W. and Y.W. did the cell culture and protein expression studies, gene sequencing and protein blot analysis. J.M.C. and A.R.K. did the methylation analysis. M.-V.B. and G.M. did the mutagenesis, bacterial protein expression and structural analysis. J.E.P. provided pathologic analysis of autopsy material.

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Correspondence to Christopher J Klein.

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Klein, C., Botuyan, MV., Wu, Y. et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet 43, 595–600 (2011).

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