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

Nature Genetics volume 43, pages 595–600 (2011)Cite this article

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Abstract

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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Acknowledgements

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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Author notes

  1. Maria-Victoria Botuyan, Yanhong Wu and Christopher J Ward: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Division of Peripheral Nerve Diseases, Mayo Clinic, Rochester, Minnesota, USA

    Christopher J Klein, William J Litchy, P James B Dyck & Peter J Dyck

  2. Mayo Clinic, Biochemistry and Molecular Biology, Rochester, Minnesota, USA

    Maria-Victoria Botuyan & Georges Mer

  3. Mayo Clinic, Laboratory Medicine and Pathology, Rochester, Minnesota, USA

    Yanhong Wu, Julie M Cunningham & David I Smith

  4. Mayo Clinic, Nephrology and Hypertension Research, Rochester, Minnesota, USA

    Christopher J Ward

  5. University of Sydney, Molecular Medicine Laboratory and Australian and New Zealand Army Corps (ANZAC) Research Institute, Australia

    Garth A Nicholson

  6. Department of Neurology, Southampton University Hospitals National Health Service (NHS) Trust, Southampton, UK

    Simon Hammans

  7. Division of Neuropsychiatry, Harima Sanatorium, Hyogo, Japan

    Kaori Hojo & Hiromitch Yamanishi

  8. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA

    Adam R Karpf

  9. Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California, USA

    Douglas C Wallace & Mariella Simon

  10. Queensland Health, Royal Brisbane Hospital, Herston, Australia

    Cecilie Lander

  11. Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA

    Lisa A Boardman

  12. Division of Psychology, Mayo Clinic, Rochester, Minnesota, USA

    Glenn E Smith

  13. Roche Applied Science Genomic Sequencing, Indianapolis, Indiana, USA

    Benjamin Boes

  14. Mayo Clinic, Biomedical Informatics and Statistics, Rochester, Minnesota, USA

    Elizabeth J Atkinson & Sumit Middha

  15. Division of Neuropathology Rochester, Mayo Clinic, Minnesota, USA

    Joseph E Parisi

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  1. Christopher J Klein
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Contributions

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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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/ng.830

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