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

Mayo Clinic, Department of Neurology, Division of Peripheral Nerve Diseases, Rochester, Minnesota, USA.
Nature Genetics (Impact Factor: 29.65). 06/2011; 43(6):595-600. DOI: 10.1038/ng.830
Source: PubMed

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.

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    • "Patient III-2 of Kindred 6 (C353F) is undergoing hemodialysis; the renal failure in Patient I-1 of Kindred 3 (Y524D) was attributed to amyloidosis due to chronic osteomyelitis, but this was not documented . A patient from the previously reported kindred (Klein et al., 2011) with Y495C also died of renal failure after chronic pyelonephritis; the kidneys showed an atrophied cortex and large numbers of nodules. At this point it remains unclear if the renal involvement is an accidental feature or in fact causally linked with DNMT1 mutations. "
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    • "People with HSN1E develop hearing loss that is caused by abnormalities in the inner ear leading to sensorineural hearing loss (Wright and Dyck, 1995; Hojo et al., 1999; Klein et al., 2011). Hearing loss worsens over time and usually progresses to moderate or severe deafness between the ages of 20 and 35 (Wright and Dyck, 1995; Hojo et al., 1999; Klein et al., 2011). Mutations in DNMT1 typically cause bilateral hearing loss but unilateral hearing loss has also been reported (Melberg et al., 1995). "
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    • "Epigenetic modifications such as histone acetylation and DNA methylation play a paramount role in regulating gene expression and exhibit unique changes during aging and age-related disease (Fraga et al., 2007; Johnson et al., 2012). Modifications to epigenetic machinery can directly impact longevity (Lin et al., 2005) and health (Klein et al., 2011) as well as prevent differentiation of stem cells into somatic tissues "
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