Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E

Sun, Zhifu; Wu, Yanhong; Ördög, Tamás; Baheti, Saurabh; Nie, Jinfu; Duan, Xiaohui; Hojo, Kaori; Kocher, Jean Pierre A.; Dyck, Peter J.; Klein, Christopher J.

doi:10.4161/epi.29676

Cited by 56 publications

(64 citation statements)

References 32 publications

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“…However, the data from HSAN1E patients indicate that DNMT1 is probably not the only actor in DNAme maintenance at DNA repeats as previously suggested in the mouse . Hypomethylation in HSAN1E also affects intergenic regions and transcription start sites, significantly enriched on chromosomes X and 18 . The differentially methylated regions (DMR) in these patients have been linked to “neurological disease” with the most compromised pathway being NAD + /NADH metabolism, which is implicated in neurodegeneration .…”

Section: Mutations In Dna Methyltransferases: Direct Impact On Dna Mementioning

confidence: 77%

“…18 Hypomethylation in HSAN1E also affects intergenic regions and transcription start sites, significantly enriched on chromosomes X and 18. 19 The differentially methylated regions (DMR) in these patients have been linked to "neurological disease" with the most compromised pathway being NAD + /NADH metabolism, which is implicated in neurodegeneration. 19 In ADCA-DN cells, the most remarkable feature reported was a DNAme gain at around 80 CGI promoters usually unmethylated in normal cells.…”

Section: Dnmt1 Mutations In Neuropathiesmentioning

confidence: 99%

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Genetics meets DNA methylation in rare diseases

Velasco

Francastel

2018

Clinical Genetics

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Alterations in epigenetic landscapes are hallmarks of many complex human diseases, yet, it is often challenging to assess the underlying mechanisms and causal link with clinical manifestations. In this regard, monogenic diseases that affect actors of the epigenetic machinery are of considerable interest to learn more about the etiology of complex traits. Spectacular breakthroughs in medical genetics are largely the result of advances in genome‐wide approaches to identify genomic and epigenomic alterations in patients. These approaches have enabled the identification of an ever‐increasing number of hereditary disorders caused by defects in the establishment of epigenetic marks early during development or in the perpetuation of such marks at later stages. We focus our review on particular cases where DNA methylation landscapes are altered at the genome scale, whether it is a direct consequence of mutations in DNA methyltransferases (DNMT) or that it reflects initial alterations of chromatin states or guiding factors caused by mutations in chromatin modifiers or transcription factors. Collectively, increased knowledge of these rare diseases will add to our understanding of the genetic determinants of DNA methylation in humans. Moreover, investigating how perturbations to these determinants affect genome function has far‐reaching potential to understand various complex human diseases.

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Section: Mutations In Dna Methyltransferases: Direct Impact On Dna Mementioning

confidence: 77%

Section: Dnmt1 Mutations In Neuropathiesmentioning

confidence: 99%

Genetics meets DNA methylation in rare diseases

Velasco

Francastel

2018

Clinical Genetics

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“…Furthermore, a mitochondrial dysfunction at the biochemical level was already documented in skeletal muscle of an ADCA-DN patient in Melberg et al (1995). In addition, the alteration of NAD + /NADH-related pathways that emerged from the methylome study on HSN1E (Sun et al, 2014) also reinforces the possibility of mitochondrial dysfunction in the complex pathogenesis of this disorder.…”

Section: Adca-dn and Hsn1e: Defective Methylation Diseases With Mitocmentioning

confidence: 79%

Dna Methyltransferase 1 Mutations and Mitochondrial Pathology: Is Mtdna Methylated?

et al. 2015

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Autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5)-methyltransferase 1 (DNMT1). DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy, and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however, mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed?

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“…This process is likely dependent on regulation of DNA methylation through DNA Methyltransferases (Dnmts), as knockdown of Dnmt3a was linked to impaired development of the inner ear in zebrafish 51 . Another key DNA methylation gene, Dnmt1, harbors a mutation linked to hereditary sensory and autonomic neuropathy type 1 (HSAN1E; OMIM 614116) [69] and autosomal dominant cerebellar ataxia, deafness, with narcolepsy (ADCA-DN; OMIM 604121), both involve deafness with late onset, suggesting a close connection between DNA methylation and the maintenance of tissue function and not necessarily the correct formation of the tissue.…”

Section: Inner Ear Sensory Epithelium Methylomes Are Unique In Comparmentioning

confidence: 99%

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

Yizhar-Barnea

Valensisi

Kishore

et al. 2018

Preprint

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Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E

Cited by 56 publications

References 32 publications

Genetics meets DNA methylation in rare diseases

Genetics meets DNA methylation in rare diseases

Dna Methyltransferase 1 Mutations and Mitochondrial Pathology: Is Mtdna Methylated?

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

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