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01 januari 2023, Item does not contain fulltext, PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access), PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Contains fulltext : 202928.pdf (publisher's version ) (Open Access), Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Molecular dynamics simulations and protein structure prediction are essential tools in the quest for better understanding of the behavior of complex proteins. Based on these insights, new drugs can be designed to help fight diseases. Here we present a GPU implementation and analysis of adaptively restrained particle simulations (ARPS), which is up to fourteen times faster than conventional full dynamics molecular dynamics implementations on the GPU. Furthermore, we present a protein deformation algorithm which allows interactive manipulation of macromolecular graphs in accordance with popular force fields such as CHARMM, based on recent advances in graphics free form deformation. These two algorithms allow for longer and larger simulations, thus greatly enhancing the power of molecular simulations.

Déposé en mars 2003 et étendu en mars 2004, info:eu-repo/semantics/published

Continuing our development of artificial models for photosystem II in green plants, a series of compounds have been prepared in which a RU(bpy)(3)(2+) photosensitizer is covalently Linked to a manganese(II) electron donor. In addition to a trispicolylamin, Addresses: Berg KE, Univ Uppsala, Dept Phys Chem, Box 532, S-75121 Uppsala, Sweden. Univ Uppsala, Dept Phys Chem, S-75121 Uppsala, Sweden. Stockholm Univ, Dept Organ Chem, S-10691 Stockholm, Sweden. Odense Univ, Dept Chem, DK-5230 Odense, Denmark. Univ Lu

Continuing our development of artificial models for photosystem II in green plants, a series of compounds have been prepared in which a RU(bpy)(3)(2+) photosensitizer is covalently Linked to a manganese(II) electron donor. In addition to a trispicolylamine Ligand, two other manganese Ligands, dipicolylamine and aminodiacetic acid, have been introduced in order to study Ligands that are appropriate for the construction of manganese dimers with open coordination sites for the binding of water. Coordination equilibria of the manganese ions were monitored by EPR. The interactions between the ruthenium and manganese moieties were probed by flash photolysis, cyclic voltammetry and steady-state and time-resolved emission measurements. The quenching of the Ru-II excited state by Mn-II was found to be rapid in complexes with short Ru-Mn distances. Nevertheless, each Run species could be photo-oxidized by bimolecular quenching with methylviologen, and the subsequent electron transfer from Mn-II to Ru-III could be monitored., QC 20100525