Bioinformatics analyses show dysregulation of calcium-related genes in Angelman syndrome mouse model.

BACKGROUND: Angelman syndrome (AS) is a genetic neurodevelopmental disorder caused by the loss of function of the UBE3A protein in the brain. In a previous study, we showed that activity-dependent calcium dynamics in hippocampal CA1 pyramidal neurons of AS mice is compromised, and its normalization rescues the hippocampal-dependent deficits. Therefore, we expected that the expression profiles of calcium-related genes would be altered in AS mice hippocampi. METHODS: We analyzed mRNA sequencing data from AS model mice and WT controls in light of the newly published CaGeDB database of calcium-related genes. We validated our results in two independent RNA sequencing datasets from two additional different AS models: first one, a human neuroblastoma cell line where UBE3A expression was knocked down by siRNA, and the second, an iPSC-derived neurons from AS patient and healthy donor control. FINDINGS: We found signatures of dysregulated calcium-related genes in AS mouse model hippocampus. Additionally, we show that these calcium-related genes function as signatures for AS in other human cellular models of AS, thus strengthening our findings. INTERPRETATION: Our findings suggest the downstream implications and significance of the compromised calcium signaling in Angelman syndrome. Moreover, since AS share similar features with other autism spectrum disorders, we believe that these findings entail meaningful data and approach for other neurodevelopmental disorders, especially those with known alterations of calcium signaling. FUNDING: This work was supported by the Angelman Syndrome Foundation and by the Israel Science Foundation, Grant Number 248/20.

Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures.

Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed that calcium signaling is disrupted in AS, and we identified calcium-target and calcium-regulating gene signatures that are able to differentiate between AS and their controls in different models. In the herein study, we evaluated these sets of calcium-target and calcium-regulating genes as signatures of AS-like and non-AS-like syndromes. We collected a number of RNA-seq datasets of various AS-like and non-AS-like syndromes and performed Principle Component Analysis (PCA) separately on the two sets of signature genes to visualize the distribution of samples on the PC1-PC2 plane. In addition to the evaluation of calcium signature genes, we performed differential gene expression analyses to identify calcium-related genes dysregulated in each of the studied syndromes. These analyses showed that the calcium-target and calcium-regulating signatures differentiate well between AS-like syndromes and their controls. However, in spite of the fact that many of the non-AS-like syndromes have multiple differentially expressed calcium-related genes, the calcium signatures were not efficient classifiers for non-AS-like neurodevelopmental disorders. These results show that features based on clinical presentation are reflected in signatures derived from bioinformatics analyses and suggest the use of bioinformatics as a tool for classification.

Effects of the Interaction between Dietary Vitamin D3 and Vitamin K3 on Growth, Skeletal Anomalies, and Expression of Bone and Calcium Metabolism-Related Genes in Juvenile Gilthead Seabream (Sparus aurata).

The interaction between vitamin D and vitamin K is crucial for regulating bone metabolism and maintaining calcium homeostasis across diverse animal species due to their complementary roles in calcium metabolism and bone health. However, research on this interaction of vitamin D and K in fish, particularly Mediterranean species like gilthead seabream, is limited or not studied. This study aimed to understand the effects of different dietary combinations of vitamin D3 and K3 on juvenile gilthead seabream. Accordingly, seabream juveniles were fed with varying combinations of vitamin D3/vitamin K3 (mg/kg diet) for 3 months: (0.07/0.01), (0.20/0.58), (0.19/1.65), (0.51/0.74), (0.56/1.00). At the end of the trial, survival, growth, body morphology, serum calcitriol, and vertebral mineral composition remained unaffected by varying vitamin levels, while gene expression patterns related to bone formation, resorption, and calcium regulation in various tissues were significantly influenced by both vitamins and their interaction. Gilthead seabream juveniles fed the 0.07/0.01 mg/kg diet upregulated calcium-regulating genes in the gills, indicating an effort to enhance calcium absorption to compensate for dietary deficiencies. Conversely, an increase in vitamin D3 and K3 up to 0.19 and 1.65 mg/kg, respectively, upregulated bone formation, bone remodeling, and calcium homeostasis-related gene expression in vertebra and other tissues. On the contrary, a dietary increase in these vitamins up to 0.56 mg/kg vitamin D3 and 1.00 mg/kg vitamin K3 downregulated calcium metabolism-related genes in tissues, suggesting an adverse interaction resulting from elevated levels of these vitamins in the diet. Hence, sustaining an equilibrium in the dietary intake of vitamin D3 and vitamin K3, in an appropriately combined form, may potentially induce interactions between the vitamins, contributing to favorable effects on bone development and calcium regulation in gilthead seabream juveniles.