TY - JOUR
T1 - Abnormalities of the DNA methylation mark and its machinery
T2 - An emerging cause of neurologic dysfunction
AU - Weissman, Jacqueline
AU - Naidu, Sakkubai
AU - Bjornsson, Hans T.
N1 - Publisher Copyright:
© 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned writers and also the readers of the methyl mark, such as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency or overexpression of DNA methylation machinery leads to widespread gene expression changes in trans, disrupting expression of a subset of target genes that contribute to individual disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome have been thought generally to cause epigenetic dysregulation in cis. However, the recent description of multilocus methylation disorders challenges this generalization. Here, in addition to summarizing recent developments in identifying the pathogenesis of these diseases, we highlight clinical considerations and some unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical imprinting disorders.
AB - Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned writers and also the readers of the methyl mark, such as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency or overexpression of DNA methylation machinery leads to widespread gene expression changes in trans, disrupting expression of a subset of target genes that contribute to individual disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome have been thought generally to cause epigenetic dysregulation in cis. However, the recent description of multilocus methylation disorders challenges this generalization. Here, in addition to summarizing recent developments in identifying the pathogenesis of these diseases, we highlight clinical considerations and some unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical imprinting disorders.
KW - Angelman syndrome
KW - Rett syndrome
KW - imprinting
KW - intellectual disability
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U2 - 10.1055/s-0034-1386763
DO - 10.1055/s-0034-1386763
M3 - Article
C2 - 25192503
AN - SCOPUS:84923616927
VL - 34
SP - 249
EP - 257
JO - Seminars in Neurology
JF - Seminars in Neurology
SN - 0271-8235
IS - 3
ER -