Sleep disturbances are a common, still poorly characterized feature of Kleefstra syndrome (KLEFS1), a neurodevelopmental disorder caused by rare variants in the epigenetic regulator EHMT1. The gap in understanding the characteristics and origin of these sleep disturbances poses a major barrier for therapy development. In this cross-species study, we reveal that 70% of individuals with KLEFS1 experience severe sleep maintenance insomnia, marked by fragmented sleep due to frequent night awakenings. Furthermore, common genetic variation at the EHMT1 locus was associated with short sleep and insomnia symptoms in the general population. Drosophila mutants of the EHMT1 orthologue G9a recapitulate these phenotypes, exhibiting reduced and fragmented sleep. We show that G9a is required in insulin-producing cells (IPCs) and the fat body, in the latter during development, to ensure adult sleep integrity. Untargeted metabolomics revealed widespread metabolic dysregulation in G9a mutants, particularly affecting methionine metabolism. Mutants exhibited reduced methionine and elevated methionine sulfoxide (Met-SO), pointing to increased reactive oxygen species (ROS). Redox sensors revealed increased H2O2-dependent oxidation in the larval brain and an elevated glutathione redox potential in IPCs during development but not in adulthood. IPC-specific knockdown of MsrA, the enzyme that reduces Met-SO back to methionine, reproduced sleep fragmentation. Developmental, but not acute, antioxidant treatment fully restored adult sleep consolidation, demonstrating that G9a safeguards sleep via ROS homeostasis in early life. Finally, we show that a Drosophila sleep-restriction paradigm based on human sleep-restriction therapy can override the developmental defects and restore sleep continuity in adulthood. Our findings establish an evolutionarily conserved role for EHMT1/G9a in sleep regulation and provide a mechanistic framework to understand and treat sleep disturbances in KLEFS1.
Mireia Coll-Tané, Lara V. van Renssen, Nicholas Raun et al.· bioRxiv· 0 citations
Externalizing and internalizing behaviours capture heritable, transdiagnostic dimensions of psychopathology, but their genetic architecture and links to societal outcomes remain incompletely understood. This study applied a multivariate framework to population-based, non-clinical traits to explore simultaneous genetic associations across externalizing and internalizing behaviours to elucidate their biological underpinnings and genetic relation to clinical diagnoses. Using genomic structural equation modelling, we built a two-factor model for externalizing (EXT) and internalizing (INT) behaviour utilizing 13 genome-wide association study (GWAS) summary statistics from population-based cohorts (n=64,000-1,200,000). We tested genetic correlations of EXT and INT with 12 psychiatric diagnoses (n=14,000-2,000,000) using linkage-disequilibrium score regression, and we studied genetic relation to emotional well-being with polygenic score analyses (PRS-CS) in an independent cohort (n= 4,565). Multivariate GWAS revealed 184 genome-wide significant loci for EXT and 31 for INT. Gene-level analyses identified 52 novel genes for EXT and 18 for INT. Enrichment analyses using single-cell-RNA-sequencing data showed significant enrichment in neuronal and non-neuronal populations, with strongest signals in hippocampal CA4 for EXT and amygdalar excitatory neurons for INT. EXT correlated with attention-deficit/hyperactivity disorder and substance-use disorders, INT showed significant genetic correlations with obsessive-compulsive disorder and anorexia nervosa. EXT and INT also exhibited overlap in genetic correlations with posttraumatic stress disorder, major depressive disorder, schizophrenia, and anxiety disorder. PRS-CS demonstrated association of INT liability with emotional well-being. Overall, these findings advance our understanding of the genetic architecture underlying transdiagnostic externalizing and internalizing behaviours and underscore their relevance for both psychiatric risk and emotional well-being.
B. Šakić, M. Klein, N. Roth Mota et al.· European Neuropsychopharmaco...· 0 citations
An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.
Marina Boon, Meghan R. Mulligan, Jolijn J. A. Verseput et al.· American Journal of Human Ge...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
