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.
authors.affiliation: Mayo Clinic, Department of Neurology, Division of Peripheral Nerve Diseases, Rochester, Minnesota, USA. klein.christopher@mayo.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Klein
authors.forename: Maria-Victoria
authors.initials: MV
authors.lastname: Botuyan
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ward
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Simon
authors.initials: S
authors.lastname: Hammans
authors.forename: Kaori
authors.initials: K
authors.lastname: Hojo
authors.forename: Hiromitch
authors.initials: H
authors.lastname: Yamanishi
authors.forename: Adam R
authors.initials: AR
authors.lastname: Karpf
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.forename: Mariella
authors.initials: M
authors.lastname: Simon
authors.forename: Cecilie
authors.initials: C
authors.lastname: Lander
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Glenn E
authors.initials: GE
authors.lastname: Smith
authors.forename: William J
authors.initials: WJ
authors.lastname: Litchy
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boes
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Atkinson
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.forename: P James
authors.initials: PJ
authors.lastname: B Dyck
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
authors.forename: David I
authors.initials: DI
authors.lastname: Smith
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
mesh_terms: D000293:Adolescent; D000328:Adult; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D003704:Dementia / Q000235:genetics; D005260:Female; D016195:G2 Phase; D034381:Hearing Loss / Q000235:genetics; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation
chemical_list: D006570:Heterochromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human