Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment.

Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26-28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, are differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit increased proliferation and cell-cycle alterations. Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multielectrode array. Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

Correlation of enthesitis indices with disease activity and function in axial and peripheral spondyloarthritis: a crosssectional study comparing MASES, SPARCC and LEI

Abstract Background: The presence of enthesitis is associated with higher disease activity, more disability and incapacity to work and a poorer quality of life in spondyloarthritis (SpA). There is currently no consensus on which clinical score should be used to assess enthesitis in SpA. The objective of the present work was to compare the correlation of three enthesitis indices (MASES, SPARCC and LEI) with measures of disease activity and function in a heterogeneous population of patients with axial and peripheral SpA. Methods: A cross-sectional study was conducted in three Brazilian public university hospitals; patients fulfilling ASAS classification criteria for peripheral or axial SpA were recruited and measures of disease activity and function were collected and correlated to three enthesitis indices: MASES, SPARCC and LEI using Spearman's Correlation index. ROC curves were used to determine if the the enthesitis indices were useful to discriminate patients with active disease from those with inactive disease. Results: Two hundred four patients were included, 71.1% (N = 145) fulfilled ASAS criteria for axial SpA and 28.9% (N = 59) for peripheral SpA. In axial SpA, MASES performed better than LEI (p = 0.018) and equal to SPARCC (p = 0.212) regarding correlation with disease activity (BASDAI) and function (BASFI). In peripheral SpA, only MASES had a weak but statistical significant correlation with DAS28-ESR (rs 0.310 p = 0.05) and MASES had better correlation with functional measures (HAQ) than SPARCC (p = 0.034). Conclusion: In this sample composed of SpA patients with high coexistence of axial and peripheral features, MASES showed statistical significant correlation with measures of disease activity and function in both axial and peripheral SpA.(AU)