Unique profile of academic learning difficulties in Wiedemann–Steiner syndrome

Funding Information: R.N. and H.T.B. are supported by grants from the Wiedemann‐Steiner Syndrome Foundation. J.A.F. acknowledges support from The Hartwell Foundation (Individual Biomedical Research Award) and the National Institute of Child Health and Development (NICHD)(K08HD086250). J.H. acknowledges support from the NICHD (K23HD101646). R.N. also received research support from NICHD (P50HD103538). Publisher Copyright: © 2022 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.Background: Wiedemann–Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non-verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent-report screening measure. Participants and Methods: A total of 25 parents of children/adults with a molecularly-confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent-screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. Results: On average, parent ratings on the Math (mean Z = -3.08, SD = 0.87) and Spatial scales (mean Z = -2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = -1.31, SD = 1.46) (Wilcoxon sign rank test Z < −3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. Conclusions: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis.Peer reviewe

Subglacial Drainage Evolution Modulates Seasonal Ice Flow Variability of Three Tidewater Glaciers in Southwest Greenland

B.J.D was funded in the form of a PhD studentship provided by the Scottish Association for Geosciences, Environment and Society (SAGES) and the University of St Andrews, UK. J.M.L is supported by a UKRI Future Leaders Fellowship (Grant No. MR/S017232/1). D.F would like to acknowledge the support of this work through the EPSRC and ESRC Centre for Doctoral Training on Quantification and Management of Risk and Uncertainty in Complex Systems Environments Grant No. (EP/L015927/1).Surface‐derived meltwater can access the bed of the Greenland Ice Sheet, causing seasonal velocity variations. The magnitude, timing and net impact on annual average ice flow of these seasonal perturbations depends on the hydraulic efficiency of the subglacial drainage system. We examine the relationships between drainage system efficiency and ice velocity, at three contrasting tidewater glaciers in southwest Greenland during 2014‐2019, using high‐resolution remotely sensed ice velocities, modelled surface melting, subglacial discharge at the terminus and results from buoyant plume modelling. All glaciers underwent a seasonal speed‐up, which usually coincided with surface melt‐onset, and subsequent slow‐down, which usually followed inferred subglacial channelisation. The amplitude and timing of these speed variations differed between glaciers, with the speed‐up being larger and more prolonged at our fastest study glacier. At all glaciers, however, the seasonal variations in ice flow are consistent with inferred changes in hydraulic efficiency of the subglacial drainage system, and qualitatively indicative of a flow regime in which annually‐averaged ice velocity is relatively insensitive to inter‐annual variations in meltwater supply – so‐called ‘ice flow self‐regulation’. These findings suggest that subglacial channel formation may exert a strong control on seasonal ice flow variations, even at fast‐flowing tidewater glaciers.Publisher PDFPeer reviewe

Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1

Kabuki syndrome is a Mendelian disorder of the epigenetic machinery characterized by typical dysmorphic features, intellectual disability, and postnatal growth deficiency. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. In addition, 11 cases of KS1 caused by mosaic variants in KMT2D have been reported in the literature. Some of these individuals display milder craniofacial and growth phenotypes, and most do not have congenital heart defects. We report the case of an infant with severe hypoplastic left heart syndrome with mitral atresia and aortic atresia (HLHS MA-AA), pulmonary vein stenosis, and atypical facies with a somatic mosaic de novo nonsense variant in KMT2D (c.8200C\u3eT, p.R2734*) identified on trio exome sequencing of peripheral blood and present in 11.2% of sequencing reads. KS was confirmed with EpiSign, a diagnostic genome-wide DNA methylation platform used to identify epigenetic signatures. This case suggests that use of this newly available clinical test can guide the interpretation of low-level mosaic variants identified through sequencing and suggests a new lower limit of mosaicism in whole blood required for a diagnosis of KS

Electrical Hole Transport Properties of an Ambipolar Organic Compound With Zn-Atoms on a Crystalline Silicon Heterostructure

In this paper, we investigate the electrical hole transport properties of an organic/inorganic heterostructure consisting of a thin organic film, that combines hole and electron conducting molecules around a bridging Zn-atom, deposited on top of an n-type crystalline silicon substrate. Current-voltage characteristics and capacitance voltage measurements have been used for the determination of the organic layer dielectric and hole conduction parameters

Retargeting the Coxsackievirus and Adenovirus Receptor to the Apical Surface of Polarized Epithelial Cells Reveals the Glycocalyx as a Barrier to Adenovirus-Mediated Gene Transfer

Lumenal delivery of adenovirus vectors (AdV) results in inefficient gene transfer to human airway epithelium. The human coxsackievirus and adenovirus receptor (hCAR) was detected by immunofluorescence selectively at the basolateral surfaces of freshly excised human airway epithelial cells, suggesting that the absence of apical hCAR constitutes a barrier to adenovirus-mediated gene delivery in vivo. In transfected polarized Madin-Darby canine kidney cells, wild-type hCAR was expressed selectively at the basolateral membrane, whereas hCAR lacking the transmembrane and/or cytoplasmic domains was expressed on both the basolateral and apical membranes. Cells expressing apical hCAR still were not efficiently transduced by AdV applied to the apical surface. However, after the cells were treated with agents that remove components of the apical surface glycocalyx, AdV transduction occurred. These results indicate that adenovirus can infect via receptors located at the apical cell membrane but that the glycocalyx impedes interaction of AdV with apical receptors

Five years of experience in the Epigenetics and Chromatin Clinic : what have we learned and where do we go from here?

Funding Information: None of the authors had specific funding for this publication, but JRH is supported by grants from the NIH/NICHD 1K23HD101646, the Kabuki Syndrome Foundation, the Rubinstein-Taybi Syndrome Children’s Foundation, the Sekel-Breidenstein Family Fund, and the Kennedy Krieger IDDRC NIH P50HD103538. HTB is supported by the Louma G. Foundation, the Icelandic Research Fund (#217988, #195835, #206806) and the Icelandic Technology Development Fund (#2010588), and JAF is supported by the National Institutes of Health, specifically the National Institute for Child Health and Human Development (NICHD; K08HD086250), the Maryland Stem Cell Research Fund (2022-MSCRFL-5846), and a Johns Hopkins Catalyst Award. CWG receives support from NIH T32GM136577. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.Peer reviewe

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved

Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood. Here, we examine the role of STIM2 in SOCE redox regulation. Redox proteomics identify cysteine 313 as the main redox sensor of STIM2 in vitro and in vivo. Oxidative stress suppresses SOCE and calcium currents in cells overexpressing STIM2 and ORAI1, an effect that is abolished by mutation of cysteine 313. FLIM and FRET microscopy, together with MD simulations, indicate that oxidative modifications of cysteine 313 alter STIM2 activation dynamics and thereby hinder STIM2-mediated gating of ORAI1. In summary, this study establishes STIM2-controlled redox regulation of SOCE as a mechanism that affects several calcium-regulated physiological processes, as well as stress-induced pathologies

The Histone Database: an integrated resource for histones and histone fold-containing proteins

Eukaryotic chromatin is composed of DNA and protein components—core histones—that act to compactly pack the DNA into nucleosomes, the fundamental building blocks of chromatin. These nucleosomes are connected to adjacent nucleosomes by linker histones. Nucleosomes are highly dynamic and, through various core histone post-translational modifications and incorporation of diverse histone variants, can serve as epigenetic marks to control processes such as gene expression and recombination. The Histone Sequence Database is a curated collection of sequences and structures of histones and non-histone proteins containing histone folds, assembled from major public databases. Here, we report a substantial increase in the number of sequences and taxonomic coverage for histone and histone fold-containing proteins available in the database. Additionally, the database now contains an expanded dataset that includes archaeal histone sequences. The database also provides comprehensive multiple sequence alignments for each of the four core histones (H2A, H2B, H3 and H4), the linker histones (H1/H5) and the archaeal histones. The database also includes current information on solved histone fold-containing structures. The Histone Sequence Database is an inclusive resource for the analysis of chromatin structure and function focused on histones and histone fold-containing proteins