Genetic diseases caused byDNMT3A germline variants and research progress on molecular mechanisms
赵桂玉 1刘月芳2
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作者信息
1. 淮安市妇幼保健院产科，淮安 223002
2. 淮安市妇幼保健院医学遗传与产前诊断科，淮安 223002
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摘要
DNMT3A胚系突变可引起两种遗传性疾病即Tatton-Brown-Rahman综合征(Tatton-Brown-Rahman syndrome，TBRS)和Heyn-Sproul-Jackson综合征，这两种疾病表型部分相反但是其潜在分子机制尚未完全阐明。本综述主要对DNMT3A基因胚系变异导致这两组疾病的分子机制研究进展进行综述。在TBRS中，DNMT3A基因PWWP功能域变异主要通过抑制其在H3K36me2富集区域定位降低mCpG水平，在神经系统，DNMT3A基因变异还可降低mCpA水平从而抑制MeCP2的结合。在Heyn-Sproul-Jackson综合征中，DNMT3A基因PWWP功能域的另外一些位点变异不仅抑制其在H3K36me2富集区域定位，同时还增强其在H2AK119ub区域富集。对DNMT3A基因变异导致出生缺陷的分子机制充分研究对该类疾病的靶向治疗具有重要意义。 Germline variants of DNMT3A define Tatton-Brown-Rahman syndrome (TBRS) and Heyn-Sproul-Jackson syndrome, which have opposite clinical features but the underlying molecular mechanisms have not been fully elucidated.This review mainly reviews the progress of research on the molecular mechanisms of TBRS and Heyn-Sproul-Jackson syndrome. In TBRS, the variants in DNMT3A PWWP domain mainly reduces mCpG levels by inhibiting its localization in H3K36me2-enriched regions.In the nervous system, DNMT3A gene variants can also reduce mCpA levels and inhibit MeCP2 binding. In Heyn-Sproul-Jackson syndrome, some variants in DNMT3A PWWP domain not only inhibited its localization in the H3K36me2-enriched region, but also enhanced its enrichment in the H2AK119ub region. Understanding the mechanisms of birth defects caused by DNMT3A germline variants may guide the design of targeted therapy.
Abstract
Germline variants of DNMT3A define Tatton-Brown-Rahman syndrome (TBRS) and Heyn-Sproul-Jackson syndrome, which have opposite clinical features but the underlying molecular mechanisms have not been fully elucidated.This review mainly reviews the progress of research on the molecular mechanisms of TBRS and Heyn-Sproul-Jackson syndrome. In TBRS, the variants in DNMT3A PWWP domain mainly reduces mCpG levels by inhibiting its localization in H3K36me2-enriched regions.In the nervous system, DNMT3A gene variants can also reduce mCpA levels and inhibit MeCP2 binding. In Heyn-Sproul-Jackson syndrome, some variants in DNMT3A PWWP domain not only inhibited its localization in the H3K36me2-enriched region, but also enhanced its enrichment in the H2AK119ub region. Understanding the mechanisms of birth defects caused by DNMT3A germline variants may guide the design of targeted therapy.
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