Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
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DOI：
10.1016/j.ajhg.2019.12.007
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发表时间：
2020-02-06
影响因子：
9.8
通讯作者：
Fahrner, Jill A.
中科院分区：
文献类型：
--
作者：
Beck, David B.;Petracovici, Ana;Fahrner, Jill A.
染色质修饰酶的种系致病性变体是儿科发育障碍的常见原因。这些酶催化通过组蛋白翻译后修饰和DNA甲基化调节表观遗传的反应。DNA的胞嘧啶甲基化（5-甲基胞嘧啶[5 mC]）是典型的表观遗传标记，但尚未描述人类孟德尔DNA去甲基化障碍。在这里，我们详细描述了一种由DNA去甲基化破坏引起的孟德尔疾病。TET 3是一种甲基胞嘧啶双加氧酶，在早期合子形成、胚胎发生和神经元分化期间启动DNA去甲基化，并且在小鼠和人类中对单倍不足不耐受。我们确定并表征了8个家族中11例TET 3缺乏症，这些家族具有智力残疾和/或全球发育迟缓的共同表型特征;张力减退;自闭症特征;运动障碍;生长异常;和面部畸形。TET 3中的单等位基因移码和无义变体发生在整个编码区。单等位基因和双等位基因错义变体定位于保守残基;除了一个这样的变体之外，所有这些变体都发生在催化结构域内，并且大多数在催化活性测定中显示亚晶型功能。TET 3缺陷和表观遗传机制的其他孟德尔疾病显示出大量的表型重叠，包括智力残疾和异常生长的特征，强调了共同的疾病机制。
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.