Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders.

PURPOSE: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants. METHODS: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins. RESULTS: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein-protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1. CONCLUSION: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Accepted version (6 month embargo), submitted versio

Btbd3 expression regulates compulsive-like and exploratory behaviors in mice

BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.Brain Research Foundation seed grant (S.C.D.), a NARSAD Independent Investigator award (S.C.D.), R21-MH115395-01 (S.C.D.), Della Martin Foundation (J.A.K.), and training grants: T32 GM07839 (S.L.T.), and T32 DA07255 (S.L.T.)

Phytoavailability of lead altered by two Pelargonium cultivars grown on contrasting lead-spiked soils

This study assesses the potential of two contrasted fragrant Pelargonium cultivars to induce pH and dissolved organic carbon (DOC) changes in the soil solution, Pb speciation, and their subsequent effects on rhizosphere phytoavailable Pb.Materials and methods: Rooted plantlets were grown in special devices, floating on aerated nutrient solution in PVC tanks. This setup allows roots to be physically separated, through a mesh, from a 3-mm soil matrix layer that can be considered as rhizosphere soil. Two contrasted soils, each spiked with Pb-rich particles, emitted from a battery recycling industry, were used at total burdens of 500 and 1500 mg Pb kg−1 in addition to a control unspiked soil. Soil solution pH, phytoavailable Pb, DOC, Pb adsorption, precipitation on roots, and Pb phases in soil and plant were investigated.Results and discussion: Attar of Roses (Attar) cultivar acidified its rhizosphere by 0.4 pH units in both spiked soils. Concolor Lace (Concolor) was unable to change soil solution pH on soil-1 and increased it by 0.7 units on soil 2. Concentrations of Pb in soil solution from Attar plants were always higher than those of Concolor ones. DOC contents of both unspiked soil-1 and soil-2 without plants were not significantly different. In the case of spiked samples, DOC contents in the rhizosphere soil were increased by three and two times for Attar and Concolor, respectively, compared to the unspiked soil without plant. Both cultivars were able to increase DOC contents, independent of soil type and level of contamination. Accumulation of Pb in shoots and roots was higher in Attar as compared to Concolor due to enhanced available Pb as a result of pH and DOC modifications of the rhizosphere soil. Significant amounts of Pb were adsorbed on roots of both cultivars. X-ray elemental analysis of precipitates on roots revealed the association of Pb with P in cylinder-like structures. Extended X-ray absorption fine structure (EXAFS) spectroscopy revealed that Pb was present, to a major extent in the inorganic form, mainly as PbSO4 in the soil, whereas it was complexed with organic species within plant tissues. The conversion of Pb into organic species could decrease toxicity, may enhance plant tolerance, and could increase translocation.Conclusions: Plant-induced changes were responsible for the modification of lead phases within the soil. Immobile forms present in the source leaded particles as well as in the soils were converted into soluble species, ultimately improving the phytoavailable or soil solubilized Pb