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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 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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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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Supplementary Figures 1–7, Supplementary Tables 1–5 and Supplementary Note. (PDF 1346 kb)

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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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