Koemans Tom S, Kleefstra Tjitske, Chubak Melissa C, Stone Max H, Reijnders Margot R F, de Munnik Sonja, Willemsen Marjolein H, Fenckova Michaela, Stumpel Connie T R M, Bok Levinus A, Sifuentes Saenz Margarita, Byerly Kyna A, Baughn Linda B, Stegmann Alexander P A, Pfundt Rolph, Zhou Huiqing, van Bokhoven Hans, Schenck Annette, Kramer Jamie M
Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands.
Radboud Institute of Molecular Life Sciences, Nijmegen, The Netherlands.
PLoS Genet. 2017 Oct 25;13(10):e1006864. doi: 10.1371/journal.pgen.1006864. eCollection 2017 Oct.
Kleefstra syndrome, caused by haploinsufficiency of euchromatin histone methyltransferase 1 (EHMT1), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic facial dysmorphisms, and other variable clinical features. In addition to EHMT1 mutations, de novo variants were reported in four additional genes (MBD5, SMARCB1, NR1I3, and KMT2C), in single individuals with clinical characteristics overlapping Kleefstra syndrome. Here, we present a novel cohort of five patients with de novo loss of function mutations affecting the histone methyltransferase KMT2C. Our clinical data delineates the KMT2C phenotypic spectrum and reinforces the phenotypic overlap with Kleefstra syndrome and other related ID disorders. To elucidate the common molecular basis of the neuropathology associated with mutations in KMT2C and EHMT1, we characterized the role of the Drosophila KMT2C ortholog, trithorax related (trr), in the nervous system. Similar to the Drosophila EHMT1 ortholog, G9a, trr is required in the mushroom body for short term memory. Trr ChIP-seq identified 3371 binding sites, mainly in the promoter of genes involved in neuronal processes. Transcriptional profiling of pan-neuronal trr knockdown and G9a null mutant fly heads identified 613 and 1123 misregulated genes, respectively. These gene sets show a significant overlap and are associated with nearly identical gene ontology enrichments. The majority of the observed biological convergence is derived from predicted indirect target genes. However, trr and G9a also have common direct targets, including the Drosophila ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of ID/ASD-related disorders.
克莱夫斯特拉综合征由常染色质组蛋白甲基转移酶1（EHMT1）单倍剂量不足引起，其特征为智力残疾（ID）、自闭症谱系障碍（ASD）、特征性面部畸形以及其他可变的临床特征。除了EHMT1突变外，在另外四个基因（MBD5、SMARCB1、NR1I3和KMT2C）中也报道了新生变异，这些变异存在于具有与克莱夫斯特拉综合征重叠临床特征的个体中。在此，我们报告了一个新的队列，其中五名患者存在影响组蛋白甲基转移酶KMT2C的新生功能丧失突变。我们的临床数据描绘了KMT2C的表型谱，并强化了与克莱夫斯特拉综合征和其他相关ID疾病的表型重叠。为了阐明与KMT2C和EHMT1突变相关的神经病理学的共同分子基础，我们对果蝇KMT2C的直系同源物三体相关蛋白（trr）在神经系统中的作用进行了表征。与果蝇EHMT1的直系同源物G9a类似，蘑菇体中的trr对短期记忆是必需的。Trr染色质免疫沉淀测序（ChIP-seq）确定了3371个结合位点，主要位于参与神经元过程的基因启动子中。全神经元trr基因敲低和G9a无效突变果蝇头部的转录谱分析分别确定了613个和1123个失调基因。这些基因集显示出显著的重叠，并且与几乎相同的基因本体富集相关。观察到的大多数生物学趋同来自预测的间接靶基因。然而，trr和G9a也有共同的直接靶标，包括Arc（Arc1）的果蝇直系同源物，Arc是突触可塑性的关键调节因子。我们的数据突出了KMT2和EHMT蛋白家族之间的临床和分子趋同，这可能有助于形成一大组与ID/ASD相关疾病的分子网络。
