Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

The biostratigraphy of Flandrian tufa deposits in the Cotswold and Mendip districts

SIGLEAvailable from British Library Document Supply Centre- DSC:D68691/86 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Survey of ditches in East Anglia and south-east England for the freshwater snails Segmentina nitida and Anisus vorticulus

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State of nature

For the first time ever, the UK’s wildlife organisations have joined forces to undertake a health check of nature in the UK and its Overseas Territories. 60% of the 3,148 UK species we assessed have declined over the last 50 years and 31% have declined strongly. Half of the species assessed have shown strong changes in their numbers or range, indicating that recent environmental changes are having a dramatic impact on nature in the UK. Species with specific habitat requirements seem to be faring worse than generalist species. A new Watchlist Indicator, developed to measure how conservation priority species are faring, shows that their overall numbers have declined by 77% in the last 40 years, with little sign of recovery. Of more than 6,000 species that have been assessed using modern Red List criteria, more than one in 10 are thought to be under threat of extinction in the UK. Our assessment looks back over 50 years at most, yet there were large declines in the UK’s wildlife prior to this, linked to habitat loss. The UK’s Overseas Territories hold a wealth of wildlife of huge international importance and over 90 of these species are at high risk of global extinction. There is a lack of knowledge on the trends of most of the UK’s species. As a result, we can report quantitative trends for only 5% of the 59,000 or so terrestrial and freshwater species in the UK, and for very few of the 8,500 marine species. Much needs to be done to improve our knowledge. What we do know about the state of the UK’s nature is often based upon the efforts of thousands of dedicated volunteer enthusiasts who contribute their time and expertise to monitoring schemes and species recording. The threats to the UK’s wildlife are many and varied, the most severe acting either to destroy valuable habitat or degrade the quality and value of what remains. Climate change is having an increasing impact on nature in the UK. Rising average temperatures are known to be driving range expansion in some species, but evidence for harmful impacts is also mounting. The full report is online: www.rspb.org.uk/stateofnature We should act to save nature both for its intrinsic value and for the benefits it brings to us that are essential to our wellbeing and prosperity. Targeted conservation has produced inspiring success stories and, with sufficient determination, resources and public support, we can turn the fortunes of our wildlife around. The State of Nature report serves to illustrate that with shared resolve and commitment we can save nature

Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability [ID] syndrome) (MIM# 300966) caused by pathogenic variants involving the X‐linked gene TATA‐box binding protein associated factor 1 (TAF1), which participates in RNA polymerase II transcription. The initial study reported 11 families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into ID and/or autism spectrum disorder. We have now identified an additional 27 families through a genotype‐first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modeling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of the TAF1/MRXS33 ID syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for a gene mapping to chromosome X