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

Christopher J. Klein; Maria Victoria Botuyan; Yanhong Wu; Christopher J. Ward; Garth A. Nicholson; Simon Hammans; Kaori Hojo; Hiromitch Yamanishi; Adam R. Karpf; Douglas C. Wallace; Mariella Simon; Cecilie Lander; Lisa A. Boardman; Julie M. Cunningham; Glenn E. Smith; William J. Litchy; Benjamin Boes; Elizabeth J. Atkinson; Sumit Middha; P. James B Dyck; Joseph E. Parisi; Georges Mer; David I. Smith; Peter J. Dyck

doi:10.1038/ng.830

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

Christopher J. Klein, Maria Victoria Botuyan, Yanhong Wu, Christopher J. Ward, Garth A. Nicholson, Simon Hammans, Kaori Hojo, Hiromitch Yamanishi, Adam R. Karpf, Douglas C. Wallace, Mariella Simon, Cecilie Lander, Lisa A. Boardman, Julie M. Cunningham, Glenn E. Smith, William J. Litchy, Benjamin Boes, Elizabeth J. Atkinson, Sumit Middha, P. James B DyckJoseph E. Parisi, Georges Mer, David I. Smith, Peter J. Dyck

Research output: Contribution to journal › Article › peer-review

289 Scopus citations

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.

Original language	English (US)
Pages (from-to)	595-600
Number of pages	6
Journal	Nature Genetics
Volume	43
Issue number	6
DOIs	https://doi.org/10.1038/ng.830
State	Published - Jun 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Klein, C. J., Botuyan, M. V., Wu, Y., Ward, C. J., Nicholson, G. A., Hammans, S., Hojo, K., Yamanishi, H., Karpf, A. R., Wallace, D. C., Simon, M., Lander, C., Boardman, L. A., Cunningham, J. M., Smith, G. E., Litchy, W. J., Boes, B., Atkinson, E. J., Middha, S., ... Dyck, P. J. (2011). Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nature Genetics, 43(6), 595-600. https://doi.org/10.1038/ng.830

Klein, CJ, Botuyan, MV, Wu, Y, Ward, CJ, Nicholson, GA, Hammans, S, Hojo, K, Yamanishi, H, Karpf, AR, Wallace, DC, Simon, M, Lander, C, Boardman, LA, Cunningham, JM, Smith, GE, Litchy, WJ, Boes, B, Atkinson, EJ, Middha, S, B Dyck, PJ, Parisi, JE, Mer, G, Smith, DI & Dyck, PJ 2011, 'Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss', Nature Genetics, vol. 43, no. 6, pp. 595-600. https://doi.org/10.1038/ng.830

@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",

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T1 - Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss

AU - Klein, Christopher J.

AU - Botuyan, Maria Victoria

AU - Wu, Yanhong

AU - Ward, Christopher J.

AU - Nicholson, Garth A.

AU - Hammans, Simon

AU - Hojo, Kaori

AU - Yamanishi, Hiromitch

AU - Karpf, Adam R.

AU - Wallace, Douglas C.

AU - Simon, Mariella

AU - Lander, Cecilie

AU - Boardman, Lisa A.

AU - Cunningham, Julie M.

AU - Smith, Glenn E.

AU - Litchy, William J.

AU - Boes, Benjamin

AU - Atkinson, Elizabeth J.

AU - Middha, Sumit

AU - B Dyck, P. James

AU - Parisi, Joseph E.

AU - Mer, Georges

AU - Smith, David I.

AU - Dyck, Peter J.

N1 - 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.

PY - 2011/6

Y1 - 2011/6

N2 - 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.

AB - 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.

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

Abstract

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