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DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.

ABSTRACT: Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20-21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has been documented in an HSAN1E family, but memory loss has been the primary cognitive complaint. The chromosomal location of the DNMT1 gene at 19p13.2 has been linked to familial late-onset Alzheimer disease.We sequenced 41 exons of DNMT1 and their flanking regions in 1) 2 kindreds with HSAN1E; 2) 48 patients with HSAN1 alone without dementia and hearing loss; and 3) 5 probands of familial frontotemporal dementia (FTD) kindreds. We also sequenced exon 20 and 21 in 364 autopsy-confirmed late-onset Alzheimer disease cases.Mutations in DNMT1 were specific to 2 HSAN1E kindreds with dementia and hearing loss (no narcolepsy). One family carried previously identified mutation Tyr495Cys; the other carried a novel Tyr495His, both in the TS domain. The symptoms of these patients include prominent personality, psychiatric manifestations, and seizures in one and the onset time is later than the previously reported cases.Clinicians should consider DNMT1 mutations in patients presenting with FTD or primary memory decline who also have sensory neuropathy and hearing loss. Amino acid Tyr495 is a hot spot for HSAN1E, distinct from exon 21 mutations associated with narcolepsy.

SUBMITTER: Klein CJ

PROVIDER: S-EPMC3598458 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.

Klein Christopher J CJ Bird Tom T Ertekin-Taner Nilufer N Lincoln Sarah S Hjorth Robert R Wu Yanhong Y Kwok John J Mer Georges G Dyck Peter J PJ Nicholson Garth A GA

Neurology 20130130 9

<h4>Background</h4>Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20-21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has been documented in an HSAN1E family, but memory ...[more]

PMID: 23365052

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Project description:DNA methyltransferase 1 (DNMT1) is essential for DNA methylation, gene regulation and chromatin stability. We previously discovered DNMT1 mutations cause hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss (HSAN1E; OMIM 614116). HSAN1E is the first adult-onset neurodegenerative disorder caused by a defect in a methyltransferase gene. HSAN1E patients appear clinically normal until young adulthood, then begin developing the characteristic symptoms involving central and peripheral nervous systems. Some HSAN1E patients also develop narcolepsy and it has recently been suggested that HSAN1E is allelic to autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), which is also caused by mutations in DNMT1. A hotspot mutation Y495C within the targeting sequence domain of DNMT1 has been identified among HSAN1E patients. The mutant DNMT1 protein shows premature degradation and reduced DNA methyltransferase activity. Herein, we investigate genome-wide DNA methylation at single-base resolution through whole-genome bisulfite sequencing of germline DNA in 3 pairs of HSAN1E patients and their gender- and age-matched siblings. Over 1 billion 75-bp single-end reads were generated for each sample. In the 3 affected siblings, overall methylation loss was consistently found in all chromosomes with X and 18 being most affected. Paired sample analysis identified 564,218 differentially methylated CpG sites (DMCs; P<0.05), of which 300?134 were intergenic and 264?084 genic CpGs. Hypomethylation was predominant in both genic and intergenic regions, including promoters, exons, most CpG islands, L1, L2, Alu, and satellite repeats and simple repeat sequences. In some CpG islands, hypermethylated CpGs outnumbered hypomethylated CpGs. In 201 imprinted genes, there were more DMCs than in non-imprinted genes and most were hypomethylated. Differentially methylated region (DMR) analysis identified 5649 hypomethylated and 1872 hypermethylated regions. Importantly, pathway analysis revealed 1693 genes associated with the identified DMRs were highly associated in diverse neurological disorders and NAD+/NADH metabolism pathways is implicated in the pathogenesis. Our results provide novel insights into the epigenetic mechanism of neurodegeneration arising from a hotspot DNMT1 mutation and reveal pathways potentially important in a broad category of neurological and psychological disorders.

Project description:Hereditary hearing loss is characterized by remarkable phenotypic heterogeneity. Patients with the same pathogenic mutations may exhibit various hearing loss phenotypes. In the Chinese population, the c.235delC mutation is the most common pathogenic mutation of GJB2 and is closely related to hereditary recessive hearing loss. Here, we investigated the hearing phenotypes of patients with hearing loss associated with the homozygous c.235delC mutation, paying special attention to asymmetric interaural hearing loss. A total of 244 patients with the GJB2 c.235delC homozygous mutation encountered from 2007 to 2015 were enrolled. The severity of hearing loss was scaled with the American Speech-Language-Hearing Association (ASHA). Auditory phenotypes were analyzed, and three types of interaural asymmetry were defined based on audiograms: Type A (asymmetry of hearing loss severity), Type B (asymmetry of audiogram shape), and Type C (Type A plus Type B). Of the 488 ears (244 cases) examined, 71.93% (351) presented with profound hearing loss, 14.34% (70) with severe hearing loss, and 9.43% (46) with moderate to severe hearing loss. The most common audiogram shapes were descending (31.15%) and flat (24.18%). A total of 156 (63.93%) of the 244 patients exhibited asymmetric interaural hearing loss in terms of severity and/or audiogram shape. Type A was evident in 14 of these cases, Type B in 106, and Type C in 36. In addition, 211 of 312 ears (67.63%) in the interaural hearing asymmetry group showed profound hearing loss, and 59 (18.91%) exhibited severe hearing loss, with the most common audiogram shapes being flat (27.88%) and descending (22.12%). By contrast, in the interaural hearing symmetry group, profound hearing loss was observed in 140 ears (79.55%), and the most common audiograms were descending (46.59%) and residual (21.59%). Hearing loss associated with the GJB2 c.235delC homozygous mutation shows diverse phenotypes, and a considerable proportion of patients show bilateral hearing loss asymmetry.

Dataset Information

DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.

Publications

DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss.

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