Nature communications · 2026

De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity.

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Hnízda Aleš, Martinez-Delgado Beatriz, Sanchez-Ponce Diana, Alonso Javier, Amiel Jeanne, Attie-Bitach Tania, Bada-Navarro Ariadna, Baladron Beatriz, Bermejo-Sanchez Eva, Brinsa Vítězslav, Buková Ivana, Cazorla-Calleja Rosario, Červenková Sylvie, Chow Shanshan, Dušek Petr, Fedosieieva Olha, Fernandez-Prieto Marta, Ghosh Sourav, Gomez-Mariano Gema, Gřegořová Andrea, Hamilton Mark James, Hartmannová Hana, Hernandez-SanMiguel Esther, Herrero-Matesanz Marina, Hodaňová Kateřina, Kádek Alan, Kerkhof Jennifer, Kleefstra Tjitske, Lacombe Didier, Levy Michael A, Lopez-Martin Estrella, Lyse Ruaud, Man Petr, Marin-Reina Purificacion, Macnamara Ellen F, McConkey Haley, Melenovská Petra, Mielu Lidia M, Moore David, Steiner Mrázová Lenka, Musilová Karolína, Neffeová Kristýna, Nickl Petr, Pajuelo Reguera David, Pavlíková Martina, Pavlovičová Lea, Posada Manuel, Procházka Jan, Pysanenko Kateryna, Ramos Del Saz Sheila, Rots Dmitrijs, Rzasa Jessica, Sedláček Radislav, Stránecký Viktor, Špoutil František, Tedder Matthew L, Thompson Louise, Tifft Cynthia J, Tran Mau-Them Frederic, Trešlová Helena, Vitobello Antonio, Hilton Sarah, Campbell Christopher, Banka Siddharth, Jirák Daniel, Sadikovic Bekim, Sikora Jakub, Kmoch Stanislav, Barrero Maria J, Nosková Lenka

Аннотация

EHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency has been established as the cause of Kleefstra syndrome 1, the pathogenesis of G9a dysfunction in human disease remains largely unknown. We identified seven de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications and transcriptomic profiles similar to those of Kleefstra syndrome 1. In vitro studies reveal that these variants encode for structurally stable G9a proteins that are catalytically incompetent due to aberrant interactions either with histone H3 tail or with S-adenosylmethionine. Heterozygous mice carrying a patient-derived variant exhibit growth retardation, facial/skull dysmorphia and aberrant behavior. Here we report pathogenic EHMT2 variants that likely exert dominant-negative effect on GLP/G9a complexes and thus genocopy the EHMT1 haploinsufficiency via a distinct molecular mechanism, defining an autosomal dominant EHMT2-related Kleefstra syndrome.

Предметные рубрики MeSH

Histone-Lysine N-Methyltransferase Humans Craniofacial Abnormalities Animals Heart Defects, Congenital Chromosomes, Human, Pair 9 Intellectual Disability Mice Chromosome Deletion Hand Deformities, Congenital Female Histocompatibility Antigens Male Histones Haploinsufficiency

De novo EHMT2 variants cause an autosomal dominant EHMT2-related Kleefstra syndrome via loss of G9a methyltransferase activity.

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH