Journal Article

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

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

2011

Overview

Christopher Klein and colleagues report that DNMT1 is disrupted in hereditary sensory neuropathy with dementia and hearing loss. The mutations lead to reduced methyltransferase activity, leading to global hypomethylation and site-specific hypermethylation. DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability 1 , 2 , 3 . DNA mismatch repair, cell cycle regulation in post-mitotic neurons 4 , 5 and neurogenesis 6 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 7 , 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/208/737 / 692/699/375/365 / Adolescent / Adult / Agriculture / Amino acids / Animal Genetics and Genomics / Bacterial proteins / Bioinformatics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cell cycle / Crystal structure / Dementia / Dementia - genetics / Dementia disorders / Deoxyribonucleic acid / DNA / DNA (Cytosine-5-)-Methyltransferase 1 / DNA (Cytosine-5-)-Methyltransferases - genetics / DNA Methylation / Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology / Female / Fundamental and applied biological sciences. Psychology / G2 Phase / Gene Function / Gene mutations / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genomes / Haplotypes / Health aspects / Hearing loss / Hearing Loss - genetics / Hereditary Sensory and Autonomic Neuropathies - genetics / Heterochromatin - metabolism / Human Genetics / Humans / letter / Male / Medical imaging / Medical sciences / Methyltransferases / Middle Aged / Models, Molecular / Mortality / Mutation / Neurodegeneration / Neuropathies, Hereditary motor and sensory / Non tumoral diseases / Otorhinolaryngology. Stomatology / Physiological aspects / Risk factors / Science activities / Tomography