Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder

• Published in: PLoS genetics Vol. 13; no. 10; p. e1006864
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.10.2017; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - physiopathology; Binding Sites - genetics; Bioinformatics; Biology and Life Sciences; Brain research; Child; Chromosome Deletion; Chromosomes, Human, Pair 9 - genetics; Cognition & reasoning; Convergence; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - physiopathology; Cytoskeletal Proteins - genetics; Developmental biology; DNA-Binding Proteins - genetics; Drosophila; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Euchromatin; Female; Funding; Gene Expression Regulation; Genes; Genetics; Genomics; Haploinsufficiency; Head; Heart Defects, Congenital - genetics; Heart Defects, Congenital - physiopathology; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histones; Histones - genetics; Humans; Insects; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Laboratories; Life sciences; Male; Medical research; Memory; Mental retardation; Methyltransferases; Mutation; Nerve Tissue Proteins - genetics; Nervous system; Neuronal Plasticity - genetics; Neurosciences; Pervasive developmental disorders; Physiological aspects; Promoter Regions, Genetic; Protein families; Research and Analysis Methods; Short term memory; Supervision; Synaptic plasticity; Transcription; Ontario Canada; Canada; Netherlands
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006864

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.