Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease.
Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease.
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作者：
组蛋白赖氨酸甲基转移酶和去甲基化酶通过动态调节组蛋白赖氨酸甲基化在染色质组织和基因表达中发挥核心作用。与此一致，编码组蛋白赖氨酸甲基转移酶（KMT）和脱甲基酶（KDM）的基因参与复杂的人类综合征，称为先天性规则性病变。在这份报告中，我们提出了几条线的证据，这些基因参与发展的眼部表型，这表明，个人结构性眼缺陷，特别是当伴随着颅面，神经发育和生长异常，应检查这些基因的可能变异。我们在受发育性眼病影响的不相关家族中鉴定了KMT 2D（5）和其他四种组蛋白赖氨酸甲基转移酶/脱甲基酶（KMT 2C，SETD 1A/KMT 2F，KDM 6A和KDM 5C）中的九种杂合损伤性遗传变异，这些疾病包括Peters异常，巩膜，Axenetri-Rieger谱，小眼症和缺损。两个家庭被临床诊断为Axenovirus-Rieger综合征，两个被诊断为Peters plus样综合征;其他人在基因检测之前没有得到具体的诊断。所有9个等位基因都是新的，其中5个是从头发生的; 5个变体导致过早截短，3个是错义变化，1个是框内缺失/插入; 7个变体被归类为致病性或可能致病性，2个是意义不确定的变体。这项研究扩展了与KMT和KDM因子相关的表型谱，并强调了基因检测对正确临床诊断的重要性。
Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis.
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影响因子：
9.2
作者：
Porntaveetus T;Abid MF;Theerapanon T;Srichomthong C;Ohazama A;Kawasaki K;Kawasaki M;Suphapeetiporn K;Sharpe PT;Shotelersuk V
通讯作者：
Shotelersuk V
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
12.3
作者：
Wu C;Orozco C;Boyer J;Leglise M;Goodale J;Batalov S;Hodge CL;Haase J;Janes J;Huss JW 3rd;Su AI
通讯作者：
Su AI
影响因子：
3.5
作者：
Brookes, Emily;Laurent, Benoit;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
5.3
作者：
Anand, Deepti;Kakrana, Atul;Lachke, Salil A.
通讯作者：
Lachke, Salil A.