PXD076523

PXD076523 is an original dataset announced via ProteomeXchange.

Title	De novo heterozygous variants in EHMT2 cause a novel Kleefstra related syndrome via loss of G9a methyltransferase activity
Description	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 revealed 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 exhibited 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.
HostingRepository	PRIDE
AnnounceDate	2026-07-03
AnnouncementXML	Submission_2026-07-03_06:40:22.289.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Petr Pompach
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF SCP

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-02 12:08:55	ID requested
⏵ 1	2026-07-03 06:40:22	announced

10.1038/S41467-026-74987-W;

submitter keyword: EHMT2, Kleefstra syndrome 1, G9a proteins,EHMT1

Ales Hnizda
contact affiliation	Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital, Charles University in Prague, Czech Republic
contact email	Ales.Hnizda@lf1.cuni.cz
lab head
Petr Pompach
contact affiliation	Intitute of Biotechnology
contact email	petr.pompach@ibt.cas.cz
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/07/PXD076523

PRIDE project URI

• PRIDE
  1. PXD076523
     1. Label: PRIDE project
     2. Name: De novo heterozygous variants in EHMT2 cause a novel Kleefstra related syndrome via loss of G9a methyltransferase activity